Author: "Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8)" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8)"' showing total 61 results

Start Over Author "Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8)"

61 results on '"Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8)"'

1. Interest of the bc-GenExMiner web tool in oncology

Author: Hamza Lasla, Mario Campone, Philippe Juin, Pascal Jézéquel, Agnes Basseville, Fadoua Ben Azzouz, Wilfried Gouraud, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, SIRIC ILIAD [Angers, Nantes], and Bernardo, Elizabeth
Subjects: Prioritization, Oncology, Transcriptomique, Cancer Research, medicine.medical_specialty, Computer science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Web tool, Breast tumor, 03 medical and health sciences, Breast cancer, 0302 clinical medicine, Data visualization, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Radiology, Nuclear Medicine and imaging, Statistical analysis, Web-based tool, Biomarker discovery, Transcriptomics, Cancer du sein, 030304 developmental biology, Outil web, 0303 health sciences, business.industry, Hematology, General Medicine, medicine.disease, Expression génique, 3. Good health, 030220 oncology & carcinogenesis, Gene expression, Web resource, business
Abstract: We are taking advantage of the launch of the latest version (v4.6) of our web-based data mining tool "breast cancer gene-expression miner" (bc-GenExMiner) to take stock of its position within the oncology research landscape and to present an activity report ten years after its establishment (http://bcgenex.ico.unicancer.fr). bc-GenExMiner is an open-access, user-friendly tool for statistical mining on breast tumor transcriptomes, annotated with more than 20 clinicopathologic and molecular characteristics. The database comprises more than 16,000 patients from 64 cohorts - including TCGA, METABRIC and SCAN-B - for whom several thousands of genes have been quantified by microarrays or RNA-seq. Correlation, expression and prognostic analyses are available for targeted, exhaustive or customized explorations of queried genes. bc-GenExMiner facilitates the validation, investigation, and prioritization of discoveries and hypotheses on genes of interest. It allows users to analyse large databases, create data visualizations, and obtain robust statistical analysis, thereby accelerating biomarker discovery. Ten years after its launch, judging by the number of visits, analyses, and scientific citations of bc-GenExMiner, we conclude that this web resource serves its purpose in the international scientific community working in breast cancer research, with a never-ending rise in its use., Nous profitons de l’occasion de la mise en ligne de la dernière version (v.4.6) de l’outil web breast cancer gene-expression miner (bc-GenExMiner) pour rappeler sa place dans le paysage de la recherche en oncologie et réaliser un bilan d’activité, dix ans après sa création (http://bcgenex.ico.unicancer.fr). bc-GenExMiner est un outil web de fouille statistique de données d’expressions géniques issues du criblage du transcriptome de tumeurs du sein annotées par une vingtaine de critères clinicopathologiques et moléculaires. Sa base de données inclut plus de 16 000 patientes issues de 64 cohortes, dont les cohortes METABRIC, SCAN-B et TCGA, pour lesquelles l’expression de plusieurs milliers de gènes a été mesurée par des puces à ADN ou par RNAseq. Il est composé de trois modules : « Corrélation », « Expression » et « Pronostic », qui permettent différentes sortes d’analyses. bc-GenExMiner offre aux chercheurs des possibilités de validation, d’exploration, de hiérarchisation d’hypothèses et de découverte concernant leurs gènes d’intérêt. Il permet de s’autonomiser par rapport à l’analyse de grandes bases de données, la production de figures, d’obtenir des résultats robustes et ainsi de gagner du temps pour la découverte de biomarqueurs. Dix ans après sa mise en ligne, à en juger par le nombre de visites, d’analyses et de citations de bc-GenExMiner dans des articles scientifiques, nous pouvons conclure que cet outil web sert la communauté scientifique internationale engagée dans la recherche sur le cancer du sein, et qu’il est de plus en plus utilisé.
Published: 2021
Full Text: View/download PDF

2. Correlation between magnetic resonance, X-ray imaging alterations and histological changes in an ovine model of age-related disc degeneration

Author: Bouhsina, N, Decante, C, Hardel, J, Madec, S, Abadie, J, Hamel, A, Le Visage, C, Lesoeur, J, Guicheux, J, Clouet, J, Fusellier, M, Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Nantes - UFR Odontologie, Université de Nantes (UN), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Femme, Enfant, Adolescent [CHU Nantes] (Pôle hospitalo-universitaire PHU5 - FEA), Centre hospitalier universitaire de Nantes (CHU Nantes), Animaux modèles pour la recherche en oncologie comparée (AMaROC), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Ostéo-articulaire - Tête et cou - Odontologie - Neurochirurgie - Neurotraumatologie [CHU Nantes] (Pôle hospitalo-universitaire PHU4 - OTONN), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Santé Publique, Pharmacie et Prévention [CHU Nantes] (Pôle hospitalo-universitaire PHU11 - S3P), Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Jehan, Frederic
Subjects: [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], sheep, Lumbar Vertebrae, Magnetic Resonance Spectroscopy, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, RD1-811, X-Rays, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, x-ray imaging, degeneration, Intervertebral Disc Degeneration, Diseases of the musculoskeletal system, histology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, RC925-935, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, magnetic resonance imaging, Female, intervertebral disc, Surgery
Abstract: International audience; Sheep are one of the many animal models used to investigate the pathophysiology of disc degeneration and the regenerative strategies for intervertebral disc (IVD) disease. To date, few studies have thoroughly explored ageing of ovine lumbar IVDs. Hence, the objective of the present study was to concomitantly assess the development of spontaneous age-related lumbar IVD degeneration in sheep using X-ray, magnetic resonance imaging (MRI) as well as histological analyses. 8 young ewes (< 48 months old) and 4 skeletally mature ewes (> 48 months old) were included. Disc height, Pfirrmann and modified Pfirrmann grades as well as T2-wsi and T2 times were assessed by X-ray and MRI. The modified Boos score was also determined using histology sections. Pfirrmann (2 to 3) and modified Pfirrmann (2 to 4) grades as well as Boos scores (7 to 13) gradually increased with ageing, while T2-weighted signal intensity (1.18 to 0.75), T2 relaxation time (114.36 to 70.65 ms) and disc height (4.1 to 3.2 mm) decreased significantly. All the imaging modalities strongly correlated with the histology (p < 0.0001). The present study described the suitability of sheep as a model of age-related IVD degeneration by correlation of histological tissue alterations with the changes observed using X-ray and MRI. Given the structural similarities with humans, the study demonstrated that sheep warrant being considered as a pertinent animal model to investigate IVD regenerative strategies without induction of degeneration.
Published: 2021
Full Text: View/download PDF

3. The predictive value of patient-reported outcomes on the impact of breast cancer treatment-related quality of life

Author: Ke, Zhou, Martine, Bellanger, Sophie, Le Lann, Marie, Robert, Jean-Sebastien, Frenel, Mario, Campone, CRLCC René Gauducheau, Centre de Recherches sur l'Action Politique en Europe (ARENES), Université de Rennes (UR)-Institut d'Études Politiques [IEP] - Rennes-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Centre National de la Recherche Scientifique (CNRS), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), SIRIC ILIAD [Angers, Nantes], Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), and EHESP, SCD
Subjects: Cancer Research, value-based cancer care, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemotherapy, targeted therapy, breast cancer, Oncology, [SDV.CAN] Life Sciences [q-bio]/Cancer, quality of life, breast cancer surgery, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, patient-reported outcomes, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, radiotherapy
Abstract: PurposePatient-reported outcomes (PROs) have been widely used to measure breast cancer (BC) treatment outcomes. However, evidence is still limited on using routinely PROs to personalize treatment decision-making, including or not chemotherapy, targeted therapy, and radiotherapy. Using patient baseline PRO scores, we aimed to use PROs before treatment initiation to predict improvement or decline in health-related quality of life (HRQoL) due to treatment that they receive.MethodsIn two French cancer sites, women with non-metastatic BC completed the EORTC QLQ-C30 and QLQ-BR23 and BREAST-Q questionnaires to assess their PROs at baseline and again at 6 months. The outcome measured was post-operative change in PROs with minimal important difference for QLQ-C30 domains. We performed multivariate ordinal logistic regression to estimate the incremental probability of post-operative PRO improvements and deteriorations depending upon treatment options and baseline HRQoL.ResultsOne hundred twenty-seven women completed questionnaires. Chemotherapy had significant negative impacts on Global health status (GHS) and on physical and social functioning. Chemotherapy and radiotherapy increased patient fatigue scores after adjusting for clinical factors (p< 0.01 and p< 0.05, respectively). The incremental probability of GHS deteriorations for chemotherapy was +0.3, +0.5, and +0.34 for patients with baseline GHS scores of 40, 70, and 100, respectively. This showed that different pre-treatment PROs might predict differential effects of chemotherapy on women change in HRQoL.ConclusionPatients with different baseline PRO scores may experience dissimilar impacts from BC treatments on post-operative PROs in terms of improvements and deteriorations. Oncologists might decide to adapt the treatment option based on a given level of the negative impact. Future studies should concentrate on incorporating this information into routine clinical decision-making strategies to optimize the treatment benefit for patients.
Published: 2022
Full Text: View/download PDF

4. Identification of three subtypes of triple-negative breast cancer with potential therapeutic implications

Author: Mario Campone, Wilfried Gouraud, Hubert Hondermarck, Hamza Lasla, Andrea Gombos, Florence Dalenc, Pascal Jézéquel, Olivier Kerdraon, Jean-Luc Canon, Suzette Delaloge, Catherine Guérin-Charbonnel, Véronique Verriele, Delphine Loussouarn, Jérôme Lemonnier, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Unité Mixte de Génomique du Cancer [ICO, Saint Herblain] (Site René Gauducheau), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER-Hôpital Guillaume-et-René-Laennec [Saint-Herblain]-Hôpital Laennec, Unité de bioinfomique [ICO, Saint Herblain], UNICANCER-UNICANCER, Laboratoire d’Anatomie et Cytologie Pathologiques [ICO, Saint Herblain], School of Biomedical Sciences and Pharmacy [Callaghan, Australia], University of Newcastle [Australia] (UoN)-Hunter Medical Research Institute [Callaghan, Australia], Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Département Oncologie-Hématologie [Charleroi, Belgium], Grand Hôpital de Charleroi [Belgium], Département Oncologie Médicale [Bruxelles, Belgium], Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Département d'Oncologie Médicale [CHU Toulouse] (IUCT Oncopole - Institut Universitaire du Cancer), Centre hospitalier universitaire de Toulouse - CHU Toulouse-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), French Breast Cancer Intergroup - UCBG [Paris] (R&D UNICANCER), R&D Unicancer [Paris], Laboratoire d'anatomie et cytologie pathologiques [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Département d'oncologie médicale [Saint Herblain] (Centre René Gauducheau - ICO), Part of this study was funded by Comité Féminin 49., Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Bernardo, Elizabeth
Subjects: Molecular subtypes, Lymphocyte, Neurogenesis, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Plasma cell, Biology, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Immune system, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biomarkers, Tumor, medicine, Cluster Analysis, Humans, Metabolomics, Transcriptomics, Immunome, B cell, Triple-negative breast cancer, Neoplasm Staging, Gene Expression Profiling, Computational Biology, Molecular Sequence Annotation, Acquired immune system, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunohistochemistry, Immune checkpoint, Tumor Burden, 3. Good health, Gene expression profiling, Cancérologie, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Triple-negative, Female, Neoplasm Grading, Transcriptome, Tertiary lymphoid structures, Research Article
Abstract: Background: Heterogeneity and lack of targeted therapies represent the two main impediments to precision treatment of triple-negative breast cancer (TNBC), and therefore, molecular subtyping and identification of therapeutic pathways are required to optimize medical care. The aim of the present study was to define robust TNBC subtypes with clinical relevance. Methods: Gene expression profiling by means of DNA chips was conducted in an internal TNBC cohort composed of 238 patients. In addition, external data (n = 257), obtained by using the same DNA chip, were used for validation. Fuzzy clustering was followed by functional annotation of the clusters. Immunohistochemistry was used to confirm transcriptomics results: CD138 and CD20 were used to test for plasma cell and B lymphocyte infiltrations, respectively; MECA79 and CD31 for tertiary lymphoid structures; and UCHL1/PGP9.5 and S100 for neurogenesis. Results: We identified three molecular clusters within TNBC: one molecular apocrine (C1) and two basal-like-enriched (C2 and C3). C2 presented pro-tumorigenic immune response (immune suppressive), high neurogenesis (nerve infiltration), and high biological aggressiveness. In contrast, C3 exhibited adaptive immune response associated with complete B cell differentiation that occurs in tertiary lymphoid structures, and immune checkpoint upregulation. External cohort subtyping by means of the same approach proved the robustness of these results. Furthermore, plasma cell and B lymphocyte infiltrates, tertiary lymphoid structures, and neurogenesis were validated at the protein levels by means of histological evaluation and immunohistochemistry. Conclusion: Our work showed that TNBC can be subcategorized in three different subtypes characterized by marked biological features, some of which could be targeted by specific therapies., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2019
Full Text: View/download PDF

5. Lien entre reprogrammation métabolique et résistance à l’apoptose induites par le stroma dans les cancers du sein triple négatif

Author: Nocquet, Lisa, Louault, Kevin, Renoult, Ophelie, Bourgeais, Jérôme, Basseville, Agnes, Pecqueur, Claire, Herault, Olivier, Juin, Philippe, Souazé, Frédérique, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Endothelium Radiobiology and Targeting (CRCINA-ÉQUIPE 14), ERL 7001 LNOx (Leukemic Niche & redOx metabolism / Niche leucémique et métabolisme redOx) (LNOx), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Souazé, Frédérique, Université de Tours-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Centre National de la Recherche Scientifique (CNRS)-Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), and Université de Tours (UT)-Université de Tours (UT)
Subjects: [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021

6. Noxa, acteur majeur de la cytotoxicité du Paclitaxel dans les tumeurs mammaires

Author: Barillé-Nion, Sophie, Dumont, Alison, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Barillé-Nion, Sophie
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: National audience
Published: 2021

7. Specialized Pro-Resolving Mediators Mitigate Cancer-Related Inflammation: Role of Tumor-Associated Macrophages and Therapeutic Opportunities

Author: Margot Lavy, Vanessa Gauttier, Sophie Barillé-Nion, Christophe Blanquart, Nicolas Poirier, OSE Immunotherapeutics [Nantes], Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Barillé-Nion, Sophie, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Immunology, Inflammation, Review, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Tumor-Associated Macrophages, Animals, Humans, Medicine, Macrophage, Immunology and Allergy, cancer, tumor microenvironment, Tissue homeostasis, Tumor microenvironment, Innate immune system, business.industry, Cancer, phagocytosis, RC581-607, medicine.disease, 3. Good health, macrophages, [SDV] Life Sciences [q-bio], 030104 developmental biology, Tumor progression, inflammation, specialized pro-resolving mediators, 030220 oncology & carcinogenesis, Cancer research, Inflammation Mediators, medicine.symptom, Immunologic diseases. Allergy, business, Carcinogenesis
Abstract: International audience; Inflammation is a fundamental physiological response orchestrated by innate immune cells to restore tissue homeostasis. Specialized pro-resolving mediators (SPMs) are involved in active resolution of inflammation but when inflammation is incomplete, chronic inflammation creates a favorable environment that fuels carcinogenesis and cancer progression. Conventional cancer therapy also strengthens cancer-related inflammation by inducing massive tumor cell death that activate surrounding immune-infiltrating cells such as tumor-associated macrophages (TAMs). Macrophages are key actors of both inflammation and its active resolution due to their plastic phenotype. In line with this high plasticity, macrophages can be hijacked by cancer cells to support tumor progression and immune escape, or therapy resistance. Impaired resolution of cancer-associated inflammation supported by TAMs may thus reinforces tumor progression. From this perspective, recent evidence suggests that stimulating macrophage's pro-resolving functions using SPMs can promote inflammation resolution in cancer and improve anticancer treatments. Thus, TAMs' re-education toward an antitumor phenotype by using SPMs opens a new line of attack in cancer treatment. Here, we review SPMs' anticancer capacities with special attention regarding their effects on TAMs. We further discuss how this new therapeutic approach could be envisioned in cancer therapy.
Published: 2021
Full Text: View/download PDF

8. Three-Dimensional Imaging of Organoids to Study Primary Ciliogenesis During ex vivo Organogenesis

Author: Duclos, Maela, Prigent, Claude, Le Borgne, Roland, Guen, Vincent J, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Organoids, Mice, Imaging, Three-Dimensional, [SDV]Life Sciences [q-bio], Organogenesis, Animals, Cell Differentiation, Cilia
Abstract: International audience; Organoids are stem cell-derived three-dimensional structures that reproduce ex vivo the complex architecture and physiology of organs. Thus, organoids represent useful models to study the mechanisms that control stem cell self-renewal and differentiation in mammals, including primary ciliogenesis and ciliary signaling. Primary ciliogenesis is the dynamic process of assembling the primary cilium, a key cell signaling center that controls stem cell self-renewal and/or differentiation in various tissues. Here we present a comprehensive protocol for the immunofluorescence staining of cell lineage and primary cilia markers, in whole-mount mouse mammary organoids, for light sheet microscopy. We describe the microscopy imaging method and an image processing technique for the quantitative analysis of primary cilium assembly and length in organoids. This protocol enables a precise analysis of primary cilia in complex three-dimensional structures at the single cell level. This method is applicable for immunofluorescence staining and imaging of primary cilia and ciliary signaling in mammary organoids derived from normal and genetically modified stem cells, from healthy and pathological tissues, to study the biology of the primary cilium in health and disease.
Published: 2021
Full Text: View/download PDF

9. One‐year conditional survival of dogs and cats with invasive mammary carcinomas: A concept inspired from human breast cancer

Author: Jérôme Abadie, Florian Chocteau, Delphine Loussouarn, Valentin Mordelet, F. Nguyen, Elie Dagher, Animaux modèles pour la recherche en oncologie comparée (AMaROC), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département de Pathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Integrated Center for Oncology [Angers] (ICO), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Oncology, medicine.medical_specialty, Survival, 040301 veterinary sciences, Lymphovascular invasion, cat, Breast Neoplasms, Mammary Neoplasms, Animal, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cat Diseases, 0403 veterinary science, 03 medical and health sciences, Dogs, 0302 clinical medicine, Conditional survival, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Animals, Humans, In patient, Dog Diseases, Stage (cooking), invasive mammary carcinoma, Retrospective Studies, CATS, conditional survival, General Veterinary, business.industry, Cancer, Original Articles, 04 agricultural and veterinary sciences, medicine.disease, 3. Good health, prognosis, 030220 oncology & carcinogenesis, Cohort, dog, Cats, Original Article, Female, business, Human breast
Abstract: International audience; Numerous studies have described the prognostic factors of canine and feline mammary carcinomas (MCs), that is, variables that predict patient survival after diagnosis. But how does survival estimation evolve in patients that escaped early death from their cancer? In human oncology, conditional survival (CS), the probability of surviving X further years when cancer patients have already survived Y years, is used to analyse cancer outcomes in a long-term perspective. In this cohort of 344 dogs and 342 cats with surgically removed stage I to III invasive MCs, with a minimal follow-up of 2 years, we calculated the 1-year CS, that is, the probability for patients that have survived 1 year, to survive or to die from cancer during the subsequent year. The 1-year conditional specific survival probabilities were 59% and 48% at diagnosis of invasive MC respectively in dogs and cats, and 80% and 52% in 1-year surviving dogs and cats respectively, suggesting that 1-year surviving dogs were relatively protected from cancer-related death, whereas feline MCs remained life-threatening cancers for longer periods of time. Among the most significant parameters associated with CS in surviving dogs and cats were the nodal stage and lymphovascular invasion, as well as patient age, cancer stage and margin status in surviving dogs. By comparison, tumour size and the histological grade did not significantly alter CS probabilities in surviving dogs and cats. Conditional survival may be considered a very interesting tool for veterinary practitioners to estimate the likely outcome of cancer survivors.
Published: 2021
Full Text: View/download PDF

10. A pharmacokinetic evaluation of alpelisib for the treatment of HR+, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer

Author: Marie Robert, Mario Campone, Anne Patsouris, Cyriac Blonz, Paule Augereau, Jean-Sebastien Frenel, Marion Bertho, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Oncology, medicine.medical_specialty, Class I Phosphatidylinositol 3-Kinases, Receptor, ErbB-2, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Toxicology, PIK3CA mutation, 030226 pharmacology & pharmacy, Alpelisib, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Animals, Humans, Endocrine system, Neoplasm Metastasis, PI3K/AKT/mTOR pathway, Phosphoinositide-3 Kinase Inhibitors, Pharmacology, Fulvestrant, business.industry, Cancer, General Medicine, PI3K inhibitors, medicine.disease, Metastatic breast cancer, 3. Good health, Thiazoles, Regimen, 030220 oncology & carcinogenesis, Mutation, Female, metastatic breast cancer, business, medicine.drug, Hormone
Abstract: International audience; Introduction: In most cases, metastatic breast cancer remains an incurable disease. A PIK3CA mutation is detected in 30-40% of all hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancers. PIK3CA activating mutations have been linked to endocrine resistance. PI3K inhibitors therefore offer promising new therapeutic options for this disease. Areas covered: This review discusses the pharmacologic properties, preclinical development, clinical efficacy, and safety profile of alpelisib, a PI3K inhibitor indicated in HR+/HER2 - PIK3CA-mutated advanced breast cancer, describing current therapeutic indication and open questions. Expert opinion: Following results of the SOLAR-1 trial, alpelisib became the first PI3K inhibitor approved by the U.S. Food and Drug Administration, in combination with fulvestrant, for postmenopausal women and men with HR+/HER2 - PIK3CA-mutated advanced breast cancer following progression on or after an endocrine-based regimen. This trial showed a substantial improvement in progression-free survival. However, given the side effects of alpelisib, the treatment decision should follow a thorough benefit-risk assessment. The BYLieve trial suggests alpelisib-fulvestrant benefit after progression on CDK 4/6 inhibitors. The identification of patients that are likely to benefit the most from PI3K inhibitors is still eagerly sought.
Published: 2021
Full Text: View/download PDF

11. Triggering the resolution of inflammation with agonistic anti-ChemR23 antibody dampens inflammation-driven carcinogenesis and metastasis

Author: Gauttier, Vanessa, Lavy, Margot, Trilleaud, Charlène, Biteau, Kévin, Neyton, Stéphanie, Girault, Isabelle, Belarif, Lyssia, Mary, Caroline, Teppaz, Géraldine, Thépénier, Virginie, Blanquart, Christophe, Barillé-Nion, Sophie, Poirier, Nicolas, OSE Immunotherapeutics [Nantes], Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract: International audience; Triggering the resolution of inflammation with agonistic anti-ChemR23 antibody dampens inflammation-driven carcinogenesis and metastasis Chronic inflammation is associated with abnormal non-phlogistic clearance (efferocytosis) of apoptotic cells by macrophages and a defect of the resolution of inflammation pathways. The resolution of inflammation is an active immunological process mediated by specialized pro-resolving mediator (SPM) which target specific resolutive G-protein coupled receptors expressed by different immune cells and participate at the return to tissue homeostasis after an injury. Defects in the clearance of (chemotherapy-induced) apoptotic tumor cell debris strengthens inflammation and has been associated with exacerbated tumor growth in several preclinical models. Proresolutive therapeutic approaches, such as using exogenous resolvin E1 (RvE1), the natural lipidic proresolutive ligand of GPCR ChemR23, have been shown to dampen tumor-associated inflammation and to reduce tumor growth. We found that ChemR23 is inducible on myeloid cells by inflammatory stimuli and mainly expressed by tumor associated macrophages in melanoma and lung cancers. We identified an agonist anti-ChemR23 mAb that accelerates the resolution of inflammation in acute inflammatory model in mice. Finally, we report that agonist anti-ChemR23 mAb limits chronic inflammation in the tumor microenvironment and inhibits metastasis development.
Published: 2021

12. Unfavorable Prognostic Effects of the Stem Cell Pluripotency Factor Sox2 in Feline Invasive Mammary Carcinomas

Author: Yohan Truchot, Elie Dagher, Jérôme Abadie, Frédérique Nguyen, Animaux modèles pour la recherche en oncologie comparée (AMaROC), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Lymphovascular invasion, Mammary gland, SOX2, cat, [SDV.CAN]Life Sciences [q-bio]/Cancer, survival, Atypical hyperplasia, regulatory T cells, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, androgen receptor, Progesterone receptor, Atypia, medicine, Original Research, 030304 developmental biology, mammary carcinoma, 0303 health sciences, lcsh:Veterinary medicine, General Veterinary, business.industry, Cancer, Hyperplasia, medicine.disease, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, lcsh:SF600-1100, Veterinary Science, prognosis, FOXA1, business
Abstract: Background: Sex-determining Region Y (SRY)-box transcription factor-2 (Sox2) belongs to the “Yamanaka's factors,” necessary and sufficient to convert somatic cells into pluripotent stem cells. In breast cancers, Sox2 expression has been associated with poor prognosis, and resistance to therapy. The aims of this study were to determine the frequency of Sox2 positivity in feline invasive mammary carcinomas (FMCs), its relationships with other clinical-pathologic variables, and with patient outcomes.Materials and Methods: This study relies on a previously described retrospective cohort of 180 FMCs, diagnosed in female cats treated by mastectomy alone, with 2-year follow-up. Sox2 (clone SP76), Estrogen Receptor alpha (ER), Progesterone Receptor (PR), Ki-67, Human Epidermal growth factor Receptor 2 (HER2), Androgen Receptor (AR), Bcl-2, Forkhead box protein A1 (FOXA1), basal markers and FoxP3-positive regulatory T cells (Tregs) were detected by automated immunohistochemistry. Sox2 expression was quantitated as an index (percentage of neoplastic cells demonstrating a positive nuclear signal). The FMCs were considered Sox2-positive at threshold >42%.Results: Sox2 was not expressed in the normal mammary gland or in mammary hyperplasia without atypia, but was occasionally detected in atypical hyperplasia. In FMCs, the mean Sox2 index was 38 ± 30%, and 79/180 FMCs (44%) were Sox2-positive. Sox2 expression was associated with older age at diagnosis, lymphovascular invasion, high Ki-67 proliferation indexes, low PR and FOXA1 expression, and increased numbers of tumor-associated Tregs, but was not significantly associated with the clinical stage, histological types, and histological grade. By multivariate survival analysis, Sox2 was associated with poor cancer-specific survival (Hazard Ratio = 1.48, 95% confidence interval 1.04–2.11, p = 0.0292), independently of the pathologic tumor size, pathologic nodal stage, distant metastasis, and AR expression. A rare subgroup of FMCs characterized by an AR+Sox2–phenotype (19/180 cases, 11%) was associated with very favorable outcomes.Conclusion: Sox2 expression was associated with poor cancer-specific survival of female cats with invasive mammary carcinomas, as previously reported in human breast cancer, but was more commonly expressed in cats than reported in breast cancers. Sox2 showed complementarity with AR in FMC prognostication.
Published: 2021
Full Text: View/download PDF

13. A partial graphical model with a structural prior on the direct links between predictors and responses

Author: Frédéric Proïa, Eunice Okome Obiang, Pascal Jézéquel, Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Université d'Angers (UA), Université de Nantes (UN), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratoire Angevin de Recherche en Mathématiques (LAREMA), Université d'Angers (UA)-Centre National de la Recherche Scientifique (CNRS), SIRIC ILIAD [Angers, Nantes], Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Sciences, EDP
Subjects: FOS: Computer and information sciences, Statistics and Probability, convex optimization, Gaussian, High-dimensional linear regression, Bayesian probability, structural penalization, Mathematics - Statistics Theory, Statistics Theory (math.ST), [MATH] Mathematics [math], 01 natural sciences, Upper and lower bounds, Statistics - Applications, Synthetic data, 010104 statistics & probability, 03 medical and health sciences, symbols.namesake, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], Covariate, Linear regression, Prior probability, FOS: Mathematics, Applications (stat.AP), Graphical model, 0101 mathematics, [MATH]Mathematics [math], 030304 developmental biology, Mathematics, 0303 health sciences, sparsity, symbols, partial graphical model, Algorithm
Abstract: This paper is devoted to the estimation of a partial graphical model with a structural Bayesian penalization. Precisely, we are interested in the linear regression setting where the estimation is made through the direct links between potentially high-dimensional predictors and multiple responses, since it is known that Gaussian graphical models enable to exhibit direct links only, whereas coefficients in linear regressions contain both direct and indirect relations (due e.g. to strong correlations among the variables). A smooth penalty reflecting a generalized Gaussian Bayesian prior on the covariates is added, either enforcing patterns (like row structures) in the direct links or regulating the joint influence of predictors. We give a theoretical guarantee for our method, taking the form of an upper bound on the estimation error arising with high probability, provided that the model is suitably regularized. Empirical studies on synthetic data and a real dataset are conducted.
Published: 2021
Full Text: View/download PDF

14. bc-GenExMiner 4.5: new mining module computes breast cancer differential gene expression analyses

Author: Pascal Jézéquel, Hamza Lasla, Philippe Juin, Catherine Guérin-Charbonnel, Mario Campone, Wilfried Gouraud, Fadoua Ben Azzouz, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Université de Nantes (UN), Université d'Angers (UA), Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), SIRIC ILIAD [Angers, Nantes], CRLCC René Gauducheau, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Microarray, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Text mining, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Gene expression, Biomarkers, Tumor, medicine, Humans, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, business.industry, Apocrine, Computational Biology, medicine.disease, Gene Expression Regulation, Neoplastic, Database Tool, 030220 oncology & carcinogenesis, AcademicSubjects/SCI00960, Female, General Agricultural and Biological Sciences, business, Information Systems
Abstract: ‘Breast cancer gene-expression miner’ (bc-GenExMiner) is a breast cancer–associated web portal (http://bcgenex.ico.unicancer.fr). Here, we describe the development of a new statistical mining module, which permits several differential gene expression analyses, i.e. ‘Expression’ module. Sixty-two breast cancer cohorts and one healthy breast cohort with their corresponding clinicopathological information are included in bc-GenExMiner v4.5 version. Analyses are based on microarray or RNAseq transcriptomic data. Thirty-nine differential gene expression analyses, grouped into 13 categories, according to clinicopathological and molecular characteristics (‘Targeted’ and ‘Exhaustive’) and gene expression (‘Customized’), have been developed. Output results are visualized in four forms of plots. This new statistical mining module offers, among other things, the possibility to compare gene expression in healthy (cancer-free), tumour-adjacent and tumour tissues at once and in three triple-negative breast cancer subtypes (i.e. C1: molecular apocrine tumours; C2: basal-like tumours infiltrated by immune suppressive cells and C3: basal-like tumours triggering an ineffective immune response). Several validation tests showed that bioinformatics process did not alter the pathobiological information contained in the source data. In this work, we developed and demonstrated that bc-GenExMiner ‘Expression’ module can be used for exploratory and validation purposes. Database URL: http://bcgenex.ico.unicancer.fr
Published: 2021
Full Text: View/download PDF

15. Random forest of perfect trees: concept, performance, applications and perspectives

Author: Pascal Jézéquel, Sophie Lambert-Lacroix, Aurélie Gaultier, Faouda Ben Azzouz, Pierre Gillois, Jean-Michel Nguyen, Luisa Silva, Alexandre Moreau-Gaudry, Philippe Juin, Mario Campone, Daniel Antonioli, Bernardo, Elizabeth, Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, École Centrale de Nantes (ECN), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), CRLCC René Gauducheau, Centre hospitalier universitaire de Nantes (CHU Nantes), and Medical Informatics [Tournemire, Quartier Bellevue] (MI)
Subjects: Statistics and Probability, AcademicSubjects/SCI01060, Computer science, Decision tree, Gene Expression, [SDV.CAN]Life Sciences [q-bio]/Cancer, Logistic regression, computer.software_genre, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Node (computer science), Feature (machine learning), Molecular Biology, 030304 developmental biology, 0303 health sciences, Original Papers, Computer Science Applications, Random forest, Support vector machine, Computational Mathematics, Tree (data structure), Computational Theory and Mathematics, Data mining, Akaike information criterion, computer, 030217 neurology & neurosurgery
Abstract: Motivation The principle of Breiman's random forest (RF) is to build and assemble complementary classification trees in a way that maximizes their variability. We propose a new type of random forest that disobeys Breiman’s principles and involves building trees with no classification errors in very large quantities. We used a new type of decision tree that uses a neuron at each node as well as an in-innovative half Christmas tree structure. With these new RFs, we developed a score, based on a family of ten new statistical information criteria, called Nguyen information criteria (NICs), to evaluate the predictive qualities of features in three dimensions. Results The first NIC allowed the Akaike information criterion to be minimized more quickly than data obtained with the Gini index when the features were introduced in a logistic regression model. The selected features based on the NICScore showed a slight advantage compared to the support vector machines—recursive feature elimination (SVM-RFE) method. We demonstrate that the inclusion of artificial neurons in tree nodes allows a large number of classifiers in the same node to be taken into account simultaneously and results in perfect trees without classification errors. Availability and implementation The methods used to build the perfect trees in this article were implemented in the ‘ROP’ R package, archived at https://cran.r-project.org/web/packages/ROP/index.html. Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2021
Full Text: View/download PDF

16. Prevalence of Reproductive Disorders including Mammary Tumors and Associated Mortality in Female Dogs

Author: Emmanuel Lange, F. Nguyen, Claire Beaudu-Lange, Kevin Lecoq, Sylvain Larrat, Bernardo, Elizabeth, Clinique Vétérinaire de la Pierre Bleue [Pipriac] (CVPB), Clinique Vétérinaire Benjamin Franklin [Brech] (CVBF), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)
Subjects: medicine.medical_specialty, medicine.medical_treatment, Veterinary medicine, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, survival, Article, [SDV.CAN] Life Sciences [q-bio]/Cancer, SF600-1100, medicine, education, Radical mastectomy, Cause of death, Gynecology, Mammary tumor, education.field_of_study, General Veterinary, dog, pyometra, spaying status, mammary tumor, radical mastectomy, business.industry, Cancer, Retrospective cohort study, Pyometra, medicine.disease, Cohort, business
Abstract: International audience; Female dogs, especially intact or neutered lately, are at increased risk for reproductive disorders including mammary tumors (MTs). This retrospective study evaluated the prevalence of reproductive pathology and associated mortality in a cohort of female dogs presented at a single veterinary clinic. The medical records of female dogs born in 2000–2003 were reviewed. The study included 599 cases, of which 293 were followed up until death. Causes of death were analyzed according to the spaying status. Among the 599 female dogs, 306 were intact (51%), 50 (8%) had been spayed before 2 years of age (ES, early spaying), and 243 (41%) after 2 years (LS, late spaying). During their lifetime, 79 dogs (13.2%) developed pyometra, and 160 (26.7%) a mammary tumor. Among the 293 dogs with complete follow-up, 103 (35.1%) had at least one MT during their lifetime, of which 53 (51.5%) died of their mammary cancer. Spayed (ES + LS) female dogs had a 4-fold decreased risk of dying from mammary cancer (OR = 0.23, 95% CI 0.11–0.47, p < 0.0001) compared to intact females. In this low-sterilization rate population, MTs developed in 35.1% of female dogs over their lifetime and was the cause of death in half of them.
Published: 2021
Full Text: View/download PDF

17. Stable Isotope Abundance and Fractionation in Human Diseases

Author: Illa, Tea, Arnaud, De Luca, Anne-Marie, Schiphorst, Mathilde, Grand, Sophie, Barillé-Nion, Eric, Mirallié, Delphine, Drui, Michel, Krempf, Régis, Hankard, Guillaume, Tcherkez, Nantes Université, Bibliothèque universitaire, Réseau de Génomique des animaux d'élevage GENANIMAL - Approche intégrée combinant la génétique, la génomique et la biologie musculaire pour gérer la qualité de la viande bovine selon le potentiel de croissance des animaux et les facteurs d'élevage. - - Mugene2005 - ANR-05-GANI-0005 - GANI - VALID, Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Nantes université - UFR des Sciences et des Techniques (Nantes univ - UFR ST), Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Australian National University (ANU), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Chirurgie Digestive et Endocrinienne [CHU Nantes] (Hôtel Dieu), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), Clinique Bretéché [Nantes], Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-INSTITUT AGRO Agrocampus Ouest, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Region Pays de la Loire, Angers Loire Metropole via the research grant Connect Talent Isoseed, Centre National de la Recherche Scientifique (CNRS), European Commission., ANR-05-GANI-0005,Mugene,Approche intégrée combinant la génétique, la génomique et la biologie musculaire pour gérer la qualité de la viande bovine selon le potentiel de croissance des animaux et les facteurs d'élevage.(2005), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université de Tours (UT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université d'Angers (UA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Australian National University - Joint College of Sciences, (ANU), and Université de Tours
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, diabetes, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Microbiology, QR1-502, metal homeostasis, [SDV.CAN] Life Sciences [q-bio]/Cancer, cancer, fractionation, isotope effect, metabolic partitioning
Abstract: The natural abundance of heavy stable isotopes (13C, 15N, 18O, etc.) is now of considerable importance in many research fields, including human physiology. In fact, it varies between tissues and metabolites due to isotope effects in biological processes, that is, isotope discriminations between heavy and light isotopic forms during enzyme or transporter activity. The metabolic deregulation associated with many diseases leads to alterations in metabolic fluxes, resulting in changes in isotope abundance that can be identified easily with current isotope ratio technologies. In this review, we summarize the current knowledge on changes in natural isotope composition in samples (including various tissues, hair, plasma, saliva) found in patients compared to controls, caused by human diseases. We discuss the metabolic origin of such isotope fractionations and highlight the potential of using isotopes at natural abundance for medical diagnosis and/or prognostic.
Published: 2021
Full Text: View/download PDF

18. Unpaired PET/CT image synthesis of liver region using CycleGAN

Author: Constance Fourcade, Mario Campone, Mathieu Rubeaux, Ludovic Ferrer, Marie Lacombe, Gianmarco Santini, Noémie Moreau, Vincent Fleury, Pascal Jézéquel, Caroline Rousseau, Keosys Medical Imaging [Saint-Herblain] (KMI), Image Perception Interaction (LS2N - équipe IPI), Laboratoire des Sciences du Numérique de Nantes (LS2N), Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École Centrale de Nantes (Nantes Univ - ECN), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes université - UFR des Sciences et des Techniques (Nantes univ - UFR ST), Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Nantes Université (Nantes Univ), Nuclear Oncology (CRCINA-ÉQUIPE 13), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Integrated Center for Oncology [Angers] (ICO), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Nantes Université - École Centrale de Nantes (Nantes Univ - ECN), Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Paired Data, PET-CT, Computer science, business.industry, Pattern recognition, Image processing, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030218 nuclear medicine & medical imaging, Image synthesis, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Body region, Artificial intelligence, business, 030217 neurology & neurosurgery
Abstract: International audience; Cross-modality synthesis represent nowadays a promising application in medical image processing to manage the problem of paired data scarcity. In this work we designed and trained a CycleGAN model to generate PET/CT data from 2D slices collected from the liver body region of twelve patients. The results obtained from the six test patients show how our model can outperform baseline CycleGAN framework and effectively be used for synthesizing artificial images to be used for data augmentation or dataset completion.
Published: 2020
Full Text: View/download PDF

19. L’instabilité génomique, paramètre limitant l’efficacité des thérapies ciblées en oncologie

Author: Louise-Marie Chevalier, Frédéric Bigot, Alain Morel, Amandine Billaud, Mario Campone, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: 0301 basic medicine, Genome instability, Genomic instability, Cancer Research, Tumour heterogeneity, Instabilité génomique, Personnalisation thérapeutique, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Synthetic lethality, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Targeted therapies, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Radiology, Nuclear Medicine and imaging, Hétérogénéité tumorale, Tumorigenèse, business.industry, Hematology, General Medicine, Oncogene Addiction, Personalized medicine, 3. Good health, 030104 developmental biology, Oncology, Thérapies ciblées, 030220 oncology & carcinogenesis, Cancer cell, Tumorigenesis, Cancer research, Carcinogenesis, business
Abstract: International audience; Genomic instability is one of the main properties of tumour development, promoting first the acquisition of genetic alterations and thus carcinogenesis. Then, the chronic and anarchic proliferation of cancer cells also supports and contributes to this instability allowing a continuous evolution of the tumour. The accumulation of mutations resulting from that instability contributes to tumour heterogeneity that occurs in a specific environment. The resulting diversity of oncogenic drivers further complicates the characterization of the origin of cancer cells dysfunction and consequently therapeutic decision. However, the consideration of the molecular context in oncology has initiated the development of targeted therapies. Based on the concept of oncogene addiction and synthetic lethality, these new drugs require the characterization and identification of specific tumour biomarkers. Targeted therapies have thus considerably optimized patient management, improving efficiency and quality of life while limiting the side effects observed with conventional chemotherapies. However, despite significant clinical benefits, some major limitations to their administration remain. The study of the current issues related to these new therapeutic molecules is becoming crucial for patient management towards an improvement of personalized medicine.
Published: 2020
Full Text: View/download PDF

20. Interactions between cancer-associated fibroblasts and tumor cells promote MCL-1 dependency in estrogen receptor-positive breast cancers

Author: F. Souazé, F. Nguyen, Sophie Barillé-Nion, Céline Séveno, Mario Campone, Fabien Gautier, Olivier Kerdraon, Patricia Gomez-Bougie, Philippe Juin, K. Louault, Pascal Jézéquel, T. L. Bonneaud, Nathalie Bourgeois, Martine Amiot, Delphine Loussouarn, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Site de Recherche Intégrée sur le Cancer - SIRIC « ILIAD » [Nantes], Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Atlantic College of Veterinary Medicine, Food Science and Engineering [UNIV Nantes Angers Le Mans] (Oniris), PRES Université Nantes Angers Le Mans (UNAM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Service d’Anatomie et Cytologie Pathologiques [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Microenvironnement des niches tumorales [UNIV Tours] (CNRS GDR 3697 MicroNiT), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), This research was performed within the framework of a CIFRE grant (ANRT contract # 20150995) for K. Louault at CRCINA and ONCOTHEREX. T.L Bonneaud was supported by a fellowship from Ligue contre le cancer. This work was supported by Odyssea, Canceropole Grand Ouest (MATURE project 2017–18), ARC (R15083NN), ANR (15-CE18-0008), INCa and DGOS (SIRIC ILIAD, INCa-DGOS Inserm-12558)., ANR-15-CE18-0008,ANTINETREX,Test compagnon ex vivo pour les essais cliniques précoces d'un anticorps anti-netrin(2015), Bernardo, Elizabeth, Test compagnon ex vivo pour les essais cliniques précoces d'un anticorps anti-netrin - - ANTINETREX2015 - ANR-15-CE18-0008 - AAPG2015 - VALID, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Tours-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Cancer Research, Cell Survival, medicine.drug_class, Estrogen receptor, [SDV.CAN]Life Sciences [q-bio]/Cancer, Apoptosis, Breast Neoplasms, Article, 03 medical and health sciences, Breast cancer, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cancer-Associated Fibroblasts, Cell Line, Tumor, hemic and lymphatic diseases, Genetics, medicine, Humans, Interleukin 6, Molecular Biology, biology, Interleukin-6, medicine.disease, 3. Good health, 030104 developmental biology, Proto-Oncogene Proteins c-bcl-2, Receptors, Estrogen, Estrogen, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, Cancer research, Myeloid Cell Leukemia Sequence 1 Protein, Female, Ex vivo
Abstract: International audience; Selective inhibition of BCL-2 is expected to enhance therapeutic vulnerability in luminal estrogen receptor-positive breast cancers. We show here that the BCL-2 dependency of luminal tumor cells is nevertheless mitigated by breast cancer-associated fibroblasts (bCAFs) in a manner that defines MCL-1 as another critical therapeutic target. bCAFs favor MCL-1 expression and apoptotic resistance in luminal cancer cells in a IL-6 dependent manner while their own, robust, survival also relies on MCL-1. Studies based on ex vivo cultures of human luminal breast cancer tissues further argue that the contribution of stroma-derived signals to MCL-1 expression shapes BCL-2 dependency. Thus, MCL-1 inhibitors are beneficial for targeted apoptosis of breast tumor ecosystems, even in a subtype where MCL-1 dependency is not intrinsically driven by oncogenic pathways.
Published: 2019
Full Text: View/download PDF

21. Bcl-2 expression and prognostic significance in feline invasive mammary carcinomas: a retrospective observational study

Author: Elie Dagher, F. Nguyen, Delphine Loussouarn, Mario Campone, Dominique Fanuel, Jérôme Abadie, Animaux modèles pour la recherche en oncologie comparée (AMaROC), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service d’Anatomie et Cytologie Pathologiques [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Integrated Center for Oncology [Angers] (ICO), This work was supported by the French National Cancer Institute (INCa, Institut National du Cancer) with a grant for translational research (INCaDHOS 2010, Pr M. Campone), by a grant for PhD students from the Ministry of Education and Higher Education of Lebanon (Dr Elie Dagher), and by Roche Diagnostics GmbH, Germany, which provided financial and technical support for the immunohistochemical characterization of the carcinomas., Bernardo, Elizabeth, École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Oncology, medicine.medical_specialty, Feline mammary carcinoma, 040301 veterinary sciences, Mammary Neoplasms, Animal, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cat Diseases, 0403 veterinary science, Cohort Studies, 03 medical and health sciences, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Animals, Bcl-2, Stage (cooking), Mastectomy, 030304 developmental biology, Retrospective Studies, 0303 health sciences, CATS, Her2 expression, lcsh:Veterinary medicine, General Veterinary, Tumor size, business.industry, Cancer, Retrospective cohort study, Spontaneous animal model, 04 agricultural and veterinary sciences, General Medicine, medicine.disease, Prognosis, 3. Good health, Proto-Oncogene Proteins c-bcl-2, Cohort, Cats, Immunohistochemistry, lcsh:SF600-1100, Female, business, Research Article, Follow-Up Studies
Abstract: International audience; BACKGROUND:Cats spontaneously develop invasive mammary carcinomas with high clinical aggressiveness, and are considered relevant animal models for human breast cancer. Bcl-2 is an anti-apoptotic pro-survival protein, whose expression is associated with a favorable outcome in human breast cancer. The aim of our study was to determine the frequency of Bcl-2 expression in feline invasive mammary carcinomas (FMCs), its relationship with other clinicopathologic variables, and its prognostic value. This retrospective study included 180 FMCs, diagnosed in female cats treated by surgery only, with a 2-year follow-up post-mastectomy. Bcl-2, ER, PR, Ki-67, HER2, and CK5/6 expression were determined by automated immunohistochemistry. A receiver-operating-characteristic curve was used to set the threshold for Bcl-2 positivity.RESULTS:The cohort comprises 32% (57/180) luminal FMCs defined by ER and/or PR positivity, and 68% (123/180) triple-negative FMCs (negative for ER, PR, and HER2). Bcl-2 expression was considered as positive when at least 65% of tumor cells were immunohistochemically stained. Thirty-one out of 180 FMCs (17%) were Bcl-2-positive. There was no significant association between Bcl-2 expression, and the tumor size, nodal stage, histological grade, or ER, PR, Ki-67, HER2, and CK5/6 expression. By multivariate survival analysis (Cox proportional-hazards regression), Bcl-2 positivity in FMCs was associated with longer disease-free interval (p = 0.005, HR = 0.38), overall survival (p = 0.028, HR = 0.61), and cancer-specific survival (p = 0.019, HR = 0.54) independently of other powerful prognostic factors such as pathologic tumor size, pathologic nodal stage, and distant metastasis. The positive prognostic value of Bcl-2 was confirmed in both luminal FMCs, of which 9/57 (16%) were Bcl-2-positive, and in basal-like triple-negative (ER-, PR-, HER2-, CK5/6+) FMCs, of which 14/76 (18%) were Bcl-2-positive.CONCLUSIONS:Compared to human breast cancer, Bcl-2 positivity in feline invasive mammary carcinomas is also associated with better outcome, but is less common, and not associated with ER, PR, and HER2 expression. Cats with spontaneous Bcl-2-positive FMCs could be useful in preclinical trials evaluating anti-Bcl-2 strategies for chemoresistant luminal or triple-negative breast cancers.
Published: 2019
Full Text: View/download PDF

22. RE: Immune checkpoint profiles in luminal B breast cancer (Alliance)

Author: Catherine Guette, Anne Patsouris, Pascal Jézéquel, Philippe Juin, Mario Campone, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Unité de bioinfomique [ICO, Saint Herblain], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Département d'oncologie médicale [Saint Herblain] (Centre René Gauducheau - ICO), Senescence Escape and Soluble Markers of Cancer Progression (CRCINA-ÉQUIPE 12), UNICANCER, Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: 0303 health sciences, Cancer Research, Luminal B Breast Cancer, Cell cycle checkpoint, business.industry, Gene Expression Profiling, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease, Immune checkpoint, 3. Good health, Gene expression profiling, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, 030220 oncology & carcinogenesis, Cancer research, Biomarkers, Tumor, Medicine, Humans, business, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience; no abstract
Published: 2020
Full Text: View/download PDF

23. p53 regulates CD46 expression and measles virus infection in myeloma cells

Author: Marion Eveillard, Steven Le Gouill, Laurent Maillet, Catherine Godon, Sophie Barillé-Nion, Marc Grégoire, Martine Amiot, Astrid Vabret, David Chiron, Frédéric Tangy, Jean-François Fonteneau, Philippe Moreau, Benoit Tessoulin, Yannick Le Bris, Anne Lok, Catherine Pellat-Deceunynck, Celine Bellanger, Géraldine Descamps, Agnès Moreau-Aubry, Service d'Hématologie Clinique [CHU Nantes] (Unité d'Investigation Clinique), Centre hospitalier universitaire de Nantes (CHU Nantes), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratoire d'Hematologie [CHU de Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Virologie [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Génomique virale et vaccination, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Ligue Régionale Contre le Cancer, DHU Oncogreffe, Actions Cancer 44, L'HémaNexT (i-site NexT), SIRIC ILIAD (INCa-DGOS-Inserm_12558), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), ANR-16-IDEX-0007,NExT (I-SITE),NExT (I-SITE)(2016), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Bernardo, Elizabeth
Subjects: 0301 basic medicine, Programmed cell death, viruses, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Membrane Cofactor Protein, Measles virus, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, immune system diseases, RNA interference, hemic and lymphatic diseases, Cell Line, Tumor, microRNA, Gene expression, Humans, Gene silencing, RNA, Small Interfering, Lymphoid Neoplasia, Hematology, biology.organism_classification, Molecular biology, female genital diseases and pregnancy complications, 3. Good health, Oncolytic virus, MicroRNAs, Receptors, TNF-Related Apoptosis-Inducing Ligand, 030104 developmental biology, Cell culture, RNA Interference, Tumor Suppressor Protein p53, Multiple Myeloma, Protein Binding
Abstract: In this study, we assessed the sensitivity of myeloma cells to the oncolytic measles virus (MV) in relation to p53 using 37 cell lines and 23 primary samples. We showed that infection and cell death were correlated with CD46 expression, which was associated with TP53 status; TP53abn cell lines highly expressed CD46 and were preferentially infected by MV when compared with the TP53wt cell lines (P = .046 and P = .045, respectively). Infection of myeloma cells was fully dependent on CD46 expression in both cell lines and primary cells. In the TP53wt cell lines, but not the TP53abn cell lines, activation of the p53 pathway with nutlin3a inhibited both CD46 expression and MV infection, while TP53 silencing reciprocally increased CD46 expression and MV infection. We showed using a p53 chromatin immunoprecipitation assay and microRNA assessment that CD46 gene expression was directly and indirectly regulated by p53. Primary myeloma cells overexpressed CD46 as compared with normal cells and were highly infected and killed by MV. CD46 expression and MV infection were inhibited by nutlin3a in primary p53-competent myeloma cells, but not in p53-deficient myeloma cells, and the latter were highly sensitive to MV infection. In summary, myeloma cells were highly sensitive to MV and infection inhibition by the p53 pathway was abrogated in p53-deficient myeloma cells. These results argue for an MV-based clinical trial for patients with p53 deficiency.
Published: 2018
Full Text: View/download PDF

24. Structure-guided design of pyridoclax derivatives based on Noxa / Mcl-1 interaction mode

Author: Christophe Denoyelle, Fabien Gautier, Peggy Suzanne, Frédéric Lopez, Jade Fogha, Laurent Poulain, Anne Sophie Voisin-Chiret, Sylvain Rault, Jana Sopkova-de Oliveira Santos, Rémi Legay, Martina De Pascale, Siham Hedir, Emilie Brotin, Marcella De Giorgi, Camille Denis, Louis-Bastien Weiswald, Bogdan A. Marekha, Philippe Juin, Ludovic Carlier, Ronan Bureau, Laetitia Ligat, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER - Institut régional du Cancer [Montpellier] (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Normandie Université (NU)-Normandie Université (NU), Stress Adaptation and Tumor Escape in breast cancer - SATE (CRCINA - Département ONCO - Equipe 8), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de cancérologie de l'Ouest - Nantes (ICO Nantes), CRLCC Paul Papin-CRLCC René Gauducheau, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), The Mcl-1 European and COACH-IPP European projects have been co-funded by Normandy County Council, European Union in the framework of the ERDF-ESF operational program 2014e2020. This work was also supported by the French State, INSERM, the 'Ligue Contre le Cancer' and by the 'Cancerop^ole Nord Ouest'. Acquisition of the xCELLigence real-time activity measurement system has been supported by European Commission and Comprehensive Cancer Center F. Baclesse. Part of this work was performed using computing resources of CRIANN (Normandy, France) as well as the European Community (FEDER) for the molecular modelling software. MDP was recipient of a doctoral fellowship from the 'Ligue Contre le Cancer'and SHwas recipient of a doctoral fellowship from the French 'Ministere de l’Education Superieure et de la Recherche'. Postdoctoral fellowships of LBW, MDG and BM as well as doctoral fellowships of JF and CD were supported by the Normandy County Council., CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Bernardo, Elizabeth
Subjects: 0301 basic medicine, Programmed cell death, Pyridines, bcl-X Protein, Regulator, [SDV.CAN]Life Sciences [q-bio]/Cancer, Tumor cells, Plasma protein binding, Molecular Dynamics Simulation, Structure-Activity Relationship, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, Drug Discovery, Tumor Cells, Cultured, Humans, Structure–activity relationship, Cell Proliferation, Pharmacology, Cell Death, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Organic Chemistry, General Medicine, 3. Good health, Cell biology, 030104 developmental biology, Proto-Oncogene Proteins c-bcl-2, Apoptosis, Drug Design, Cancer cell, Myeloid Cell Leukemia Sequence 1 Protein, Interaction mode, Drug Screening Assays, Antitumor, Hydrophobic and Hydrophilic Interactions, Protein Binding
Abstract: International audience; Protein-protein interactions are attractive targets because they control numerous cellular processes. In oncology, apoptosis regulating Bcl-2 family proteins are of particular interest. Apoptotic cell death is controlled via PPIs between the anti-apoptotic proteins hydrophobic groove and the pro-apoptotic proteins BH3 domain. In ovarian carcinoma, it has been previously demonstrated that Bcl-x L and Mcl-1 cooperate to protect tumor cells against apoptosis. Moreover, Mcl-1 is a key regulator of cancer cell survival and is a known resistance factor to Bcl-2/Bcl-x L pharmacological inhibitors making it an attractive therapeutic target. Here, using a structure-guided design from the oligopyridine lead Pyr-idoclax based on Noxa/Mcl-1 interaction we identified a new derivative, active at lower concentration as compared to Pyridoclax. This new derivative selectively binds to the Mcl-1 hydrophobic groove and releases Bak and Bim from Mcl-1 to induce cell death and sensitize cancer cells to Bcl-2/Bcl-x L targeting strategies.
Published: 2018
Full Text: View/download PDF

25. Synthesis and cytotoxicity studies of newly designed benzyl-hydroquinone derivatives

Author: René Grée, Sophie Barillé-Nion, Fabien Gautier, Paul Mosset, Olivier Tasseau, Philippe Juin, Niharika Amireddy, Shasi V. Kalivendi, Nicolas Levoin, Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre de Lutte Contre le Cancer René Gauducheau, Bioprojet-Biotech, CSIR Indian Institute of Chemical Technology (IICT), Ligue contre le Cancer, Conseil Interregional Grand Ouest, University of Rennes1, University of Nantes, INSERM, CNRS, CSIR, Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Hydroquinone, Terpenes, 010405 organic chemistry, Chemistry, Organic Chemistry, Pharmacology toxicology, HCT cells, 010402 general chemistry, 01 natural sciences, Combinatorial chemistry, Hydroquinones, 3. Good health, 0104 chemical sciences, Terpene, chemistry.chemical_compound, [CHIM]Chemical Sciences, MDAMB231 cells, MDAMB468 cells, General Pharmacology, Toxicology and Pharmaceutics, Cancer cell lines, Cytotoxicity, ComputingMilieux_MISCELLANEOUS, Cancer
Abstract: A series of new benzyl-substituted hydroquinones has been prepared by short and flexible routes. Such molecules are simplified analogs of bioactive natural terpenes. Preliminary studies have established, for some of these derivatives, promising cytotoxicity data against human carcinoma cancer cell lines.
Published: 2018
Full Text: View/download PDF

26. Identification of an immune-suppressed subtype of feline triple-negative basal-like invasive mammary carcinomas, spontaneous models of breast cancer

Author: Mario Campone, F. Nguyen, Jérôme Abadie, Elie Dagher, Delphine Loussouarn, Laura Simbault, Bernardo, Elizabeth, Animaux modèles pour la recherche en oncologie comparée (AMaROC), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Anatomie Pathologique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre Hospitalier Universitaire G. R. Laennec (HGRL Saint-Herblain), Integrated Center for Oncology [Angers] (ICO), This work was supported by the French National Cancer Institute (INCa, Institut National du Cancer) with a grant for translational research (grant number INCa-DHOS 2010) (M.C.), by a grant for PhD students from the Ministry of Education and Higher Education of Lebanon (E.D.), and by Roche Diagnostics GmbH, Germany, which provided financial and technical support for the immunohistochemical characterization of the carcinomas., Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: 040301 veterinary sciences, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mammary Neoplasms, Animal, Triple Negative Breast Neoplasms, forkhead box protein P3, T-Lymphocytes, Regulatory, regulatory T cells, Feline Mammary Carcinoma, 0403 veterinary science, 03 medical and health sciences, Basal (phylogenetics), 0302 clinical medicine, Breast cancer, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Tumor Microenvironment, Animals, Humans, immune tumor microenvironment, Pathological, Gene, RC254-282, Retrospective Studies, Immunosuppression Therapy, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer, Basal-like breast cancer, 04 agricultural and veterinary sciences, General Medicine, medicine.disease, Prognosis, Immunohistochemistry, feline mammary carcinoma, 3. Good health, Disease Models, Animal, Receptors, Estrogen, Hormone receptor, 030220 oncology & carcinogenesis, Cancer research, Cats, Female, business, Receptors, Progesterone
Abstract: International audience; Feline invasive mammary carcinomas are characterized by their high clinical aggressiveness, rare expression of hormone receptors, and pathological resemblance to human breast cancer, especially triple-negative breast cancer (negative to estrogen receptor, progesterone receptor, and epidermal growth factor receptor type 2). Recent gene expression studies of triple-negative breast cancers have highlighted their heterogeneity and the importance of immune responses in their biology and prognostic assessment. Indeed, regulatory T cells may play a crucial role in producing an immune-suppressed microenvironment, notably in triple-negative breast cancers. Feline invasive mammary carcinomas arise spontaneously in immune-competent animals, in which we hypothesized that the immune tumor microenvironment also plays a role. The aims of this study were to determine the quantity and prognostic value of forkhead box protein P3-positive peritumoral and intratumoral regulatory T cells in feline invasive mammary carcinomas, and to identify an immune-suppressed subgroup of triple-negative basal-like feline invasive mammary carcinomas. One hundred and eighty female cats with feline invasive mammary carcinomas, treated by surgery only, with 2-year follow-up post-mastectomy, were included in this study. Forkhead box protein P3, estrogen receptor, progesterone receptor, Ki-67, epidermal growth factor receptor type 2, and cytokeratin 14 expression were assessed by automated immunohistochemistry. Peritumoral regulatory T cells were over 300 times more abundant than intratumoral regulatory T cells in feline invasive mammary carcinomas. Peritumoral and intratumoral regulatory T cells were associated with shorter disease-free interval and overall survival in both triple-negative (ER-, PR-, HER2-, N = 123 out of 180) and luminal (ER+ and/or PR+, N = 57) feline invasive mammary carcinomas. In feline triple-negative basal-like (CK14+) mammary carcinomas, a regulatory T-cell-enriched subgroup was associated with significantly poorer disease-free interval, overall survival, and cancer-specific survival than regulatory T-cell-poor triple-negative basal-like feline invasive mammary carcinomas. High regulatory T-cell numbers had strong and negative prognostic value in feline invasive mammary carcinomas, especially in the triple-negative basal-like subgroup, which might contain a ''basal-like immune-suppressed'' subtype, as described in triple-negative breast cancer. Cats with feline invasive mammary carcinomas may thus be interesting spontaneous animal models to investigate new strategies of cancer immunotherapy in an immune-suppressed tumor microenvironment.
Published: 2020
Full Text: View/download PDF

27. Impact of pemetrexed chemotherapy on the gut microbiota and intestinal inflammation of patient-lung-derived tumor xenograft (PDX) mouse models

Author: Hervé M. Blottière, Françoise Le Vacon, Cindy Pensec, Thomas Carton, Sébastien Leuillet, Mario Campone, Florence Gillaizeau, Anne Bessard, Michel Neunlist, Dominique Guenot, Biofortis Mérieux NutriSciences [Saint-Herblain], IMODI Consortium, Laboratory EA3430. Progression tumorale et microenvironnement, Approches Translationnelles et Epidémiologie, University of Strasbourg, 3 avenue Molière, 67000 Strasbourg, France, The Enteric Nervous System in gut and brain disorders [U1235] (TENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), French National Research Agency (ANR) IMODI Consortium, Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), This work was supported by an ANRT subvention (CIFRE fellowship) and the IMODI Consortium., and Bodescot, Myriam
Subjects: Lung Neoplasms, medicine.medical_treatment, [SDV]Life Sciences [q-bio], lcsh:Medicine, Mice, SCID, Gut flora, TOXICITY, Carcinoma, Non-Small-Cell Lung, Medicine, Intestinal Mucosa, lcsh:Science, 0303 health sciences, Multidisciplinary, biology, CANCER, 3. Good health, Specific Pathogen-Free Organisms, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Pemetrexed, OBESITY, Toxicity, BACTERIA, Heterografts, Female, medicine.symptom, medicine.drug, Tumor Graft, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Inflammation, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, digestive system, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Carcinoma, Animals, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, 030304 developmental biology, Chemotherapy, Intestinal permeability, 030306 microbiology, business.industry, lcsh:R, medicine.disease, biology.organism_classification, Gastrointestinal Microbiome, Disease Models, Animal, Cancer research, FECAL MICROBIOTA, lcsh:Q, Metagenomics, business, Non-small-cell lung cancer, Neoplasm Transplantation
Abstract: Chemotherapy remains the gold standard for advanced cancer. Pemetrexed, a chemotherapeutic agent used in non-small cell lung cancer, can induce significant side effects in patients. Although microbiota’s role in the efficacy and/or toxicity of chemotherapy agents has been demonstrated, the impacts of pemetrexed on the gut microbiota and on gastrointestinal inflammation remain unknown. The objective of this study was to evaluate the impact of pemetrexed and the tumor graft on the gut microbiota composition in immunodeficient mice. The faecal microbiota composition was studied with metabarcoding before, 24-h and one week after treatment. The colon epithelial barrier integrity was evaluated by histological examination, intestinal permeability measurement, and selected cytokines quantification. The tumor graft induced some variations in the microbiota composition. Pemetrexed further increased the relative abundance of Enterobacteriaceae and 3 families from the Firmicutes phylum: Enterococcaceae, Lactobacillaceae and Streptococcaceae. Pemetrexed also significantly altered the epithelial barrier integrity, which was associated with early inflammation. This pilot study shows that the association of a lung tumor graft with pemetrexed causes an alteration in the microbiota composition. Such information increases our knowledge about the impact of chemotherapy on the microbiota, which could help to minimize side effects and improve therapeutic effectiveness in the future.
Published: 2020
Full Text: View/download PDF

28. SPECT-CT Imaging of Dog Spontaneous Diffuse Large B-Cell Lymphoma Targeting CD22 for the Implementation of a Relevant Preclinical Model for Human

Author: Etienne, Floriane, Berthaud, Maxime, Nguyen, Frédérique, Bernardeau, Karine, Maurel, Catherine, Bodet-Milin, Caroline, Diab, Maya, Abadie, Jérôme, Gouilleux-Gruart, Valérie, Vidal, Aurélien, Bourgeois, Mickael, Chouin, Nicolas, Ibisch, Catherine, Davodeau, François, Oncologie nucléaire (CRCINA - Département NOHMAD - Equipe 13), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Animaux Modèles pour la Recherche en Oncologie [Nantes] (AMaROC), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Stress Adaptation and Tumor Escape in breast cancer - SATE (CRCINA - Département ONCO - Equipe 8), Plateforme 'Production de protéines recombinantes' (P2R - INSERM UMS016/CNRS UMS3556/UN FED4203), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Service de Médecine Nucléaire [Nantes], Hôpital Laennec, Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours, Cyclotron ARRONAX [Saint-Herblain], ARRONAX - (GIP) Groupement d'Intérêt Public [Saint-Herblain] (Institut de Recherche Public), This work was supported by the Institut Thématique MultiOrganismes (ITMO) Cancer of the Alliance pour les sciences de la vie et de la santé (AVIESAN) jointly with the Institut National du Cancer (INCA) under one grant entitled: Spontaneous tumor models in animals for translational research in oncology no. A11196NS (CANIMAB). Financial support was also provided by a Physics, Mathematics and Engineering sciences applied to the Cancer Research grant (DogPPK project) awarded by INSERM and INCa., Nuclear Oncology (CRCINA-ÉQUIPE 13), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Animaux modèles pour la recherche en oncologie comparée (AMaROC), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Université de Tours (UT), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: comparative oncology, diffuse large B-cell lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, SPECT-CT imaging, internalization, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, immune system diseases, monoclonal antibody, hemic and lymphatic diseases, dog, internalization Etienne et al Radiolabeled Anti-canine CD22 Antibodies, CD22, Original Research
Abstract: International audience; Antibodies directed against CD22 have been used in radioimmunotherapy (RIT) clinical trials to treat patients with diffuse large B-cell lymphoma (DLBCL) with promising results. However, relevant preclinical models are needed to facilitate the evaluation and optimization of new protocols. Spontaneous DLBCL in dogs is a tumor model that may help accelerate the development of new methodologies and therapeutic strategies for RIT targeting CD22. Seven murine monoclonal antibodies specific for canine CD22 were produced by the hybridoma method and characterized. The antibodies' affinity and epitopic maps, their internalization capability and usefulness for diagnosis in immunohistochemistry were determined. Biodistribution and PET imaging on a mouse xenogeneic model of dog DLBCL was used to choose the most promising antibody for our purposes. PET-CT results confirmed biodistribution study observations and allowed tumor localization. The selected antibody, 10C6, was successfully used on a dog with spontaneous DLBCL for SPECT-CT imaging in the context of disease staging, validating its efficacy for diagnosis and the feasibility of future RIT assays. This first attempt at phenotypic imaging on dogs paves the way to implementing quantitative imaging methodologies that would be transposable to humans in a theranostic approach. Taking into account the feedback of existing human radioimmunotherapy clinical trials targeting CD22, animal trials are planned to investigate protocol improvements that are difficult to consider in humans due to ethical concerns.
Published: 2020
Full Text: View/download PDF

29. Lactic acidosis together with GM-CSF and M-CSF induces human macrophages toward an inflammatory pro-tumor phenotype

Author: Laurence Preisser, Pedro Raro, Clément Adam, Pascale Pignon, Vincent Procaccio, Vincent Lavoué, Alain Morel, Philippe Descamps, Simon Blanchard, Cinzia Bocca, Valérie Seegers, Céline Beauvillain, Romuald Wernert, Judith Kouassi Nzoughet, Léa Paolini, Norbert Ifrah, Pascale Jeannin, Véronique Verrielle, Yves Delneste, Mario Campone, Véronique Catros, Louise-Marie Chevalier, Guy Lenaers, Guillaume Tcherkez, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), CHU Pontchaillou [Rennes], Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Canberra, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), INCa-DGOS-Inserm_12558, Ministry of Health and the Institute for Health and Medical Research, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'Immunologie et d'Allergologie [CHU Angers], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Ressources Biologiques Santé (CRB Santé), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), Australian National University (ANU), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), SIRIC ILIAD program (National Cancer Institute, Ministry of Health and the Institute for Health and Medical Research, INCa-DGOS-Inserm_12558)Ligue contre le Cancer (comitée du Maine et Loire, Angers, France) and the regional council of Pays de la Loire (Canceropole Grand-Ouest, projects PlasTICO and Concerto), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Innate immunity and Immunotherapy (CRCINA - Département INCIT - Equipe 7), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), Stress Adaptation and Tumor Escape in breast cancer - SATE (CRCINA - Département ONCO - Equipe 8), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), Blanchard, Simon, and Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID
Subjects: 0301 basic medicine, Cancer Research, Chemokine, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Immunology, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Monocytes, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Tumor Cells, Cultured, medicine, Humans, cancer, Interleukin 8, Autocrine signalling, ComputingMilieux_MISCELLANEOUS, Ovarian Neoplasms, lactate, biology, Chemistry, Macrophage Colony-Stimulating Factor, Macrophages, Granulocyte-Macrophage Colony-Stimulating Factor, Cell Differentiation, GM-CSF, medicine.disease, M-CSF, 3. Good health, Interleukin 10, Phenotype, 030104 developmental biology, inflammation, 030220 oncology & carcinogenesis, Monocyte differentiation, Lactic acidosis, biology.protein, Cancer research, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Acidosis, Lactic, Female, medicine.symptom
Abstract: In established tumors, tumor-associated macrophages (TAM) orchestrate nonresolving cancer-related inflammation and produce mediators favoring tumor growth, metastasis, and angiogenesis. However, the factors conferring inflammatory and protumor properties on human macrophages remain largely unknown. Most solid tumors have high lactate content. We therefore analyzed the impact of lactate on human monocyte differentiation. We report that prolonged lactic acidosis induces the differentiation of monocytes into macrophages with a phenotype including protumor and inflammatory characteristics. These cells produce tumor growth factors, inflammatory cytokines, and chemokines as well as low amounts of IL10. These effects of lactate require its metabolism and are associated with hypoxia-inducible factor-1α stabilization. The expression of some lactate-induced genes is dependent on autocrine M-CSF consumption. Finally, TAMs with protumor and inflammatory characteristics (VEGFhigh CXCL8+ IL1β+) are found in solid ovarian tumors. These results show that tumor-derived lactate links the protumor features of TAMs with their inflammatory properties. Treatments that reduce tumor glycolysis or tumor-associated acidosis may help combat cancer.
Published: 2020
Full Text: View/download PDF

30. STING-dependent paracriny shapes apoptotic priming of breast tumors in response to anti-mitotic treatment

Author: Lohard, Steven, Bourgeois, Nathalie, Maillet, Laurent, Gautier, Fabien, Fétiveau, Aurélie, Lasla, Hamza, Nguyen, Frédérique, Vuillier, Céline, Dumont, Alison, Moreau-Aubry, Agnès, Frapin, Morgane, David, Laurent, Loussouarn, Delphine, Kerdraon, Olivier, Campone, Mario, Jézéquel, Pascal, Juin, Philippe P., Barillé-Nion, Sophie, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Site de Recherche Intégrée sur le Cancer - SIRIC « ILIAD » [Nantes] (INCA-DGOS-Inserm), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Université de Nantes (UN)-Université de Nantes (UN), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Service d'Anatomie Pathologique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre Hospitalier Universitaire G. R. Laennec (HGRL Saint-Herblain), This work was supported by the Ligue contre le Cancer (44, 22, 53, 56, and 85), the Canceropole Grand Ouest, the Region Pays de la Loire (MATURE project 2017–18) and the Agence Nationale de la Recherche (Grands defis societaux 2015–2020, Antinetrex project)., Stress Adaptation and Tumor Escape in breast cancer - SATE (CRCINA - Département ONCO - Equipe 8), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Institut de cancérologie de l'Ouest - Nantes (ICO Nantes), CRLCC Paul Papin-CRLCC René Gauducheau, Regulation of Bcl2 and p53 networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA - Département NOHMAD - Equipe 10), Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Cell death, Cell biology, Paclitaxel, Science, bcl-X Protein, Apoptosis, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antimitotic Agents, Article, Cell Line, Gene Knockout Techniques, Mice, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Paracrine Communication, Tumor Cells, Cultured, Animals, Humans, lcsh:Science, Cancer, Tumor Necrosis Factor-alpha, Membrane Proteins, Nucleotidyltransferases, Xenograft Model Antitumor Assays, Proto-Oncogene Proteins c-bcl-2, Interferon Type I, lcsh:Q, Female, Signal Transduction
Abstract: A fascinating but uncharacterized action of antimitotic chemotherapy is to collectively prime cancer cells to apoptotic mitochondrial outer membrane permeabilization (MOMP), while impacting only on cycling cell subsets. Here, we show that a proapoptotic secretory phenotype is induced by activation of cGAS/STING in cancer cells that are hit by antimitotic treatment, accumulate micronuclei and maintain mitochondrial integrity despite intrinsic apoptotic pressure. Organotypic cultures of primary human breast tumors and patient-derived xenografts sensitive to paclitaxel exhibit gene expression signatures typical of type I IFN and TNFα exposure. These cytokines induced by cGAS/STING activation trigger NOXA expression in neighboring cells and render them acutely sensitive to BCL-xL inhibition. cGAS/STING-dependent apoptotic effects are required for paclitaxel response in vivo, and they are amplified by sequential, but not synchronous, administration of BH3 mimetics. Thus anti-mitotic agents propagate apoptotic priming across heterogeneously sensitive cancer cells through cytosolic DNA sensing pathway-dependent extracellular signals, exploitable by delayed MOMP targeting., Antimitotic compounds, such as paclitaxel, induce cell death in cycling cancer cells only. Here, the authors show that paclitaxel-targeted breast cancer cells prime neighboring cells to apoptosis through a STING-mediated paracrine signaling pathway.
Published: 2020
Full Text: View/download PDF

31. Dual targeting of BCL2 and MCL1 rescues myeloma cells resistant to BCL2 and MCL1 inhibitors associated with the formation of BAX/ BAK hetero-complexes

Author: Charlotte Kervoëlen, Sophie Maïga, Patricia Gomez-Bougie, Carolane Seiller, Laurent Maillet, Celine Bellanger, Philippe Moreau, Martine Amiot, Catherine Pellat-Deceunynck, Géraldine Descamps, Cyrille Touzeau, Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Site de Recherche Intégrée sur le Cancer - SIRIC « ILIAD » [Nantes] (INCA-DGOS-Inserm), Service d'Hématologie Clinique [CHU Nantes] (Unité d'Investigation Clinique), Centre hospitalier universitaire de Nantes (CHU Nantes), Plate-forme Therassay Onco-Hématologie, Capacités [UN Nantes], Université de Nantes (UN), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), This study was supported by the Fondation Française pour la Recherche contre le Myélome et les Gammapathies monoclonales (FFRMG), Ligue Grand Ouest contre le Cancer, Intergroupe Francophone du Myélome, Action Cancer 44 and the SIRIC ILIAD,INCa-DGOS-Inserm_12558., Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Cancer Research, Programmed cell death, Immunology, Antineoplastic Agents, Apoptosis, Myeloma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Thiophenes, Plasma cell, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, immune system diseases, Cell Line, Tumor, hemic and lymphatic diseases, medicine, Humans, MCL1, lcsh:QH573-671, Multiple myeloma, 030304 developmental biology, 0303 health sciences, Venetoclax, lcsh:Cytology, Cell Biology, medicine.disease, 3. Good health, medicine.anatomical_structure, Pyrimidines, chemistry, Proto-Oncogene Proteins c-bcl-2, Cell culture, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer research, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Recurrence, Local, Apoptosis Regulatory Proteins, Multiple Myeloma, Ex vivo
Abstract: Multiple myeloma is a plasma cell malignancy that escapes from apoptosis by heterogeneously over-expressing anti-apoptotic BCL2 proteins. Myeloma cells with a t(11;14) translocation present a particular vulnerability to BCL2 inhibition while a majority of myeloma cells relies on MCL1 for survival. The present study aimed to determine whether the combination of BCL2 and MCL1 inhibitors at low doses could be of benefit for myeloma cells beyond the single selective inhibition of BCL2 or MCL1. We identified that half of patients were not efficiently targeted neither by BCL2 inhibitor nor MCL1 inhibitor. Seventy percent of these myeloma samples, either from patients at diagnosis or relapse, presented a marked increase of apoptosis upon low dose combination of both inhibitors. Interestingly, primary cells from a patient in progression under venetoclax treatment were not sensitive ex vivo to neither venetoclax nor to MCL1 inhibitor, whereas the combination of both efficiently induced cell death. This finding suggests that the combination could overcome venetoclax resistance. The efficacy of the combination was also confirmed in U266 xenograft model resistant to BCL2 and MCL1 inhibitors. Mechanistically, we demonstrated that the combination of both inhibitors favors apoptosis in a BAX/BAK dependent manner. We showed that activated BAX was readily increased upon the inhibitor combination leading to the formation of BAK/BAX hetero-complexes. We found that BCLXL remains a major resistant factor of cell death induced by this combination. The present study supports a rational for the clinical use of venetoclax/S63845 combination in myeloma patients with the potential to elicit significant clinical activity when both single inhibitors would not be effective but also to overcome developed in vivo venetoclax resistance.
Published: 2020
Full Text: View/download PDF

32. Anti-PD1 therapy induces lymphocyte-derived exosomal miRNA-4315 release inhibiting Bim-mediated apoptosis of tumor cells

Author: Nina Guyon, Delphine Garnier, Joséphine Briand, Arulraj Nadaradjane, Gwenola Bougras-Cartron, Judith Raimbourg, Mario Campone, Dominique Heymann, François M. Vallette, Jean-Sébastien Frenel, Pierre-François Cartron, Bernardo, Elizabeth, Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Cancéropôle Grand-Ouest [Bretagne-Centre-Pays de Loire], EpiSAVMEN Network (Région Pays de la Loire) [Saint-Herblain], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Sulfonamides, Aniline Compounds, Bcl-2-Like Protein 11, Cell Death, lcsh:Cytology, T-Lymphocytes, Programmed Cell Death 1 Receptor, Mice, Nude, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Exosomes, Article, MicroRNAs, Phenotype, [SDV.CAN] Life Sciences [q-bio]/Cancer, Drug Resistance, Neoplasm, Cell Line, Tumor, Neoplasms, miRNAs, Biomarkers, Tumor, Temozolomide, Animals, Humans, lcsh:QH573-671, Cancer
Abstract: International audience; Anti-PD1 immunotherapy, as a single agent or in combination with standard chemotherapies, has significantly improved the outcome of many patients with cancers. However, resistance to anti-PD1 antibodies often decreases the long-term therapeutic benefits. Despite this observation in clinical practice, the molecular mechanisms associated with resistance to anti-PD1 antibody therapy have not yet been elucidated. To identify the mechanisms of resistance associated with anti-PD1 antibody therapy, we developed cellular models including purified T cells and different cancer cell lines from glioblastoma, lung adenocarcinoma, breast cancer and ovarian carcinoma. A murine model of lung cancer was also used. Longitudinal blood samples of patients treated with anti-PD1 therapy were also used to perform a proof-of-concept study of our findings. We found that anti-PD1 exposure of T-cell promotes an enrichment of exosomal miRNA-4315. We also noted that exosomal miRNA-4315 induced a phenomenon of apopto-resistance to conventional chemotherapies in cancer cells receiving exosomal miRNA-4315. At molecular level, we discern that the apopto-resistance phenomenon was associated with the miRNA-4315-mediated downregulation of Bim, a proapoptotic protein. In cellular and mice models, we observed that the BH3 mimetic agent ABT263 circumvented this resistance. A longitudinal study using patient blood showed that miRNA-4315 and cytochrome c can be used to define the time period during which the addition of ABT263 therapy may effectively increase cancer cell death and bypass anti-PD1 resistance.This work provides a blood biomarker (exosomal miRNA-4315) for patient stratification developing a phenomenon of resistance to anti-PD1 antibody therapy and also identifies a therapeutic alternative (the use of a BH3 mimetic drug) to limit this resistance phenomenon.
Published: 2020
Full Text: View/download PDF

33. Glutamine uptake and utilization of human mesenchymal glioblastoma in orthotopic mouse model

Author: Oizel, Kristell, Yang, Chendong, Renoult, Ophelie, Gautier, Fabien, Do, Quyen, Joalland, Noemie, Gao, Xiaofei, Ko, Bookyung, Vallette, François, Ge, Woo-Ping, Paris, François, DeBerardinis, Ralph, Pecqueur, Claire, Bernardo, Elizabeth, University of Texas Southwestern Medical Center [Dallas], Endothelium Radiobiology and Targeting (CRCINA-ÉQUIPE 14), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Human primary cells, Mesenchymal, urogenital system, Research, Orthotopic model, Glutamine, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, urologic and male genital diseases, lcsh:RC254-282, female genital diseases and pregnancy complications, nervous system diseases, Molecular subtype, Metabolism, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glioblastoma
Abstract: International audience; Background: Glioblastoma (GBM) are highly heterogeneous on the cellular and molecular basis. It has been proposed that glutamine metabolism of primary cells established from human tumors discriminates aggressive mesenchymal GBM subtype to other subtypes.Methods: To study glutamine metabolism in vivo, we used a human orthotopic mouse model for GBM. Tumors evolving from the implanted primary GBM cells expressing different molecular signatures were analyzed using mass spectrometry for their metabolite pools and enrichment in carbon 13 (13C) after 13C-glutamine infusion.Results: Our results showed that mesenchymal GBM tumors displayed increased glutamine uptake and utilization compared to both control brain tissue and other GBM subtypes. Furthermore, both glutamine synthetase and transglutaminase-2 were expressed accordingly to GBM metabolic phenotypes.Conclusion: Thus, our results outline the specific enhanced glutamine flux in vivo of the aggressive mesenchymal GBM subtype.
Published: 2020
Full Text: View/download PDF

34. Noxa the BCL-2 Family Member behind the Scenes in Cancer Treatment

Author: Alison Dumont, Sophie Barillé-Nion, Laurent Maillet, Steven Lohard, Philippe Juin, Bernardo, Elizabeth, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: [SDV.CAN] Life Sciences [q-bio]/Cancer, business.industry, Apoptosis, hemic and lymphatic diseases, Bcl-2 family, Cancer research, Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, business, 3. Good health, Cancer treatment
Abstract: International audience; NOXA is a critical mediator of stress responses to anticancer drugs. This BH3-only protein sets the apoptotic threshold in cancer cells in response to chemotherapies by counteracting the prosurvival BCL-2 family protein MCL-1. A complex and dynamic network relying on both highly controlled gene transcription activity and protein degradation by proteasome, regulates cellular NOXA levels from low in steady state to rapidly enhanced upon stressful condition. Antimitotics and proteasome inhibitors are powerful anticancer treatments that mainly rely on NOXA activity to trigger death in cancer cells. In addition, in case of antimitotics, a wave of cell death based on NOXA and fueled by an automomous secretome spreads through the tumor, revealing new therapeutic opportunities. By neutralizing MCL-1 prosurvival activity, NOXA induces preferential BCL-2 or BCL-xL cancer cell survival dependencies, that can be exploited therapeutically using BH3 mimetics. Since MCL-1 interfers with tumor response to chemotherapies, promoting NOXA expression or using recently available MCL-1 targeting BH3 mimetics are promising opportunities to improve cancer treatments.
Published: 2020

35. Abstract P4-06-11: High immune response identified as a good prognostic factor by proteomic SWATH-MS approach in 157 ER+/HER2- early breast cancer

Author: Anne Patsouris, Catherine Guette, Hamza Lasla, Cécile Henry, Philippe Juin, Pascal Jézéquel, Mario Campone, Alice Boissard, Senescence Escape and Soluble Markers of Cancer Progression (CRCINA-ÉQUIPE 12), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Swath ms, Prognostic factor, business.industry, [SDV.CAN]Life Sciences [q-bio]/Cancer, 3. Good health, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, business, Early breast cancer
Abstract: Background: Estrogen positive/HER2 negative (ER+/HER2-) early (e) breast carcinoma (BC) is an heterogeneous entity, on the prognostic and predictive plan. Several prognostic multigene tests have been developed to identify patients in whom chemotherapy could be safely avoided. Proteomic is a complementary approach as variations in mRNA expression only account for ≈40% of the tumor-encoded protein range and it is taking into account, as other OMICs the tumoral microenvironment Sequential Windowed Acquisition of All Theoretical fragment (SWATH-MS) proteomic approach let an accurate and reproducible label-free quantification of large proteome. To our knowledge, no study has been conducted in a large cohort of luminal BC by SWATH-MS. The aim of this study was to establish a proteomic cartography of ER+/HER2- eBC and identify prognostic biomarkers. Methods: Frozen primary tumors were collected from 157 ER+/HER2- eBC treated in the ICO cancer center between 2006 and 2009. Patients were included if they fulfilled the following criteria: 1) ductal carcinoma; 2) unilateral; 3) first occurrence; 4) have received adjuvant chemotherapy. Clinicopathologic characteristics as outcomes were collected. Each sample was analyzed using SWATH-MS acquisition method as previously described (Aebersold et al, 2012). Peak extraction of the SWATH data was performed using either the Spectronaut software (ver 8.0, Biognosys, Switzerland). Peptide identification results were filtered with a q-value of < 1%. We performed clustering analysis (fuzzy clustering method) based on the 15% of most variant proteins. Functional annotation of clusters based on GO biological process terms enrichment (GOEA) was performed by means of ToppGene and GORILLA web tools. Results: The median of follow-up was 8.34 years. Respectively 32, 4 and 7 patients presented a metastatic, locoregional and controlateral recurrence. 684 among 4555 proteins represented the 15% of most variants proteins.Two ER+/HER2- eBC clusters were identified (C1 [23%] and C2 [77%]) by means of fuzzy clustering and GOEA. Two significant clinicopathological differences were observed between the two subgroups: more unifocal tumors in C1 (P = 0.0415) and mostly a clear better outcome in term of Disease Free Survival (DFS), Distant DFS (DDFS) and Overall survival (OS) in patients belonging to C2 (cf table 1). Functional annotation found that C1 was characterized by mRNA processing and protein synthesis (GO:0006396: RNA processing; GO:0008380: RNA splicing; GO:0016071: mRNA metabolic process; GO:0022613: ribonucleoprotein complex biogenesis), and C2 by a high immune response (GO:0002757: immune response-activating signal transduction; GO:0050778: positive regulation of immune response; GO:0002253: activation of immune response; GO:0050776: regulation of immune response). Differential protein expression according to the C1-C2 clusters will be presented at the meeting. Conclusion: Proteomic cartography by SWATH-MS can clearly distinguish two ER+/HER2- eBC subgroups with clear different prognosis with a better outcome for C2 patients compared to C1 patients. High immune response observed in C2 could underlie this difference with results that must be confirmed on external cohort. Nevertheless this approach could be considered as a complementary approach, helpful for clinical decision for administration of adjuvant treatment. All (n=157)Cluster 1 (n = 36)Cluster 2 (n = 121)PDisease-free survival72%55.5%77.6%0.0016Distant disease-free survival79.6%66.6%83.4%0.0063Overall survival81%61%87%0.0009Specific overall survival86%69%91%0.0012 Citation Format: Anne Patsouris, Hamza Lasla, Pascal Jézéquel, Philippe Juin, Alice Boissard, Cécile Henry, Mario Campone, Catherine Guette. High immune response identified as a good prognostic factor by proteomic SWATH-MS approach in 157 ER+/HER2- early breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-06-11.
Published: 2019
Full Text: View/download PDF

36. Epinephrine Infiltration of Adipose Tissue Impacts MCF7 Breast Cancer Cells and Total Lipid Content

Author: Avril, Pierre, Vidal, Luciano, Barille-Nion, Sophie, Le Nail, Louis-Romée, Rédini, Françoise, Layrolle, Pierre, Pinault, Michelle, Chevalier, Stéphane, Perrot, Pierre, Trichet, Valérie, Bernardo, Elizabeth, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie Plastique et des Brulés [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), This work was partly supported by INSERM, the University of Nantes and Cancéropole Grand Ouest (AOE2016)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université Bretagne Loire (UBL)
Subjects: Mammary Neoplasms, Experimental, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Lipid Metabolism, Xenograft Model Antitumor Assays, Article, adipose tissue, lcsh:Chemistry, Mice, breast cancer, lcsh:Biology (General), lcsh:QD1-999, [SDV.CAN] Life Sciences [q-bio]/Cancer, Culture Media, Conditioned, MCF-7 Cells, Animals, Humans, breast reconstruction, Female, epinephrine, skin and connective tissue diseases, lcsh:QH301-705.5, Cell Proliferation
Abstract: Pierre Avril and Luciano Vidal contributed equally to this work.; International audience; Background: Considering the positive or negative potential effects of adipocytes, depending on their lipid composition, on breast tumor progression, it is important to evaluate whether adipose tissue (AT) harvesting procedures, including epinephrine infiltration, may influence breast cancer progression. Methods: Culture medium conditioned with epinephrine-infiltrated adipose tissue was tested on human Michigan Cancer Foundation-7 (MCF7) breast cancer cells, cultured in monolayer or in oncospheres. Lipid composition was evaluated depending on epinephrine-infiltration for five patients. Epinephrine-infiltrated adipose tissue (EI-AT) or corresponding conditioned medium (EI-CM) were injected into orthotopic breast carcinoma induced in athymic mouse. Results: EI-CM significantly increased the proliferation rate of MCF7 cells Moreover EI-CM induced an output of the quiescent state of MCF7 cells, but it could be either an activator or inhibitor of the epithelial mesenchymal transition as indicated by gene expression changes. EI-CM presented a significantly higher lipid total weight compared with the conditioned medium obtained from non-infiltrated-AT of paired-patients. In vivo, neither the EI-CM or EI-AT injection significantly promoted MCF7-induced tumor growth. Conclusions: Even though conditioned media are widely used to mimic the secretome of cells or tissues, they may produce different effects on tumor progression, which may explain some of the discrepancy observed between in vitro, preclinical and clinical data using AT samples.
Published: 2019
Full Text: View/download PDF

37. Proposal for a Histological Staging System of Mammary Carcinomas in Dogs and Cats. Part 1: Canine Mammary Carcinomas

Author: Florian Chocteau, Jérôme Abadie, Delphine Loussouarn, Frédérique Nguyen, Animaux modèles pour la recherche en oncologie comparée (AMaROC), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de Pathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Intégré d'Oncologie Nantes/Angers, This work was supported by the French National Cancer Institute (INCa, Institut National du Cancer) with a grant for translational research (INCa-DHOS 2010, Prof. M. Campone) and one grant for Ph.D. students on translational research (Grant N°201108, 2011), and by Roche Diagnostics GmbH, Germany, which provided financial and technical support for the immunohistochemical characterization of the carcinomas., Bernardo, Elizabeth, Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: pathologic tumor size, 0303 health sciences, lcsh:Veterinary medicine, General Veterinary, 040301 veterinary sciences, lymphovascular invasion, [SDV.CAN]Life Sciences [q-bio]/Cancer, 04 agricultural and veterinary sciences, stage, survival, 3. Good health, 0403 veterinary science, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, dog, lcsh:SF600-1100, Veterinary Science, pathologic nodal stage, prognosis, Original Research, 030304 developmental biology, mammary carcinoma
Abstract: International audience; Background: Staging of mammary carcinomas of dogs and cats is not only important for prognostic purposes, but also to guide therapy, in particular regarding adjuvant chemotherapy. The classical staging system relies on T, the clinical tumor size, N, the clinical nodal stage, and M, distant metastasis, evaluated by the clinician. However, a more precise and reliable staging system is applied to human stage I–III breast cancer, i.e., without distant metastasis, in which T is replaced by the pathologic tumor size (pT), and N is replaced by the pathologic nodal stage (pN), both evaluated by the pathologist. This staging system is strongly associated with patient outcomes, and is used to select treatment options. The purpose of this study was to design a histologic staging system for Canine Mammary Carcinomas (CMCs, part 1 of this article), and Feline Mammary Carcinomas (part 2), inspired from human oncology, and to assess its association with patient outcomes.Materials and Methods: This retrospective study included 433 female dogs with a surgically removed CMC. Patient outcomes were recorded over a 2-years follow up period. CMCs were staged according to pT (greatest diameter in millimeters on histological slides), lymphovascular invasion (LVI), and pN (confirmed by cytokeratin AE1/AE3 immunohistochemistry). The histological stages were defined as: Stage 0 (CMCs in situ, surrounded by a continuous layer of p63+ myoepithelial cells), Stage I (pT1 ≤ 20 mm, LVI–, pN0–pNX, where pNX refers to the absence of lymph node sample), Stage II (pT2 > 20 mm, LVI–, pN0–pNX), Stage IIIA (pT1, LVI+, and/or pN+), and Stage IIIB (pT2, LVI+, and/or pN+).Results: Disease-free-interval, overall survival and specific survival significantly differed by histological stage. For specific survival, median survival times and hazard ratios (HR) by Cox proportional hazards regression (p < 0.0001) were: Stage 0 (median survival not reached; HR = 1.00; N = 89; 21% of the dogs), Stage I (1,720 days; HR = 3.05; p = 0.0018; N = 81; 19%), Stage II (1,181 days; HR = 4.39; p < 0.0001; N = 79; 18%), Stage IIIA (348 days; HR = 10.59; p < 0.0001; N = 79; 18%), and Stage IIIB (163 days; HR = 16.59; p < 0.0001; N = 105; 24%).Conclusion: The proposed histological staging system (invasiveness, pT, LVI, pN) is a very strong prognostic factor for CMCs.
Published: 2019
Full Text: View/download PDF

38. OLFM4 Expression in Ductal Carcinoma In Situ and in Invasive Breast Cancer Cohorts by a SWATH‐Based Proteomic Approach

Author: Olivier Coqueret, Mario Campone, Isabelle Valo, Alice Boissard, Pedro Raro, Véronique Verriele, Amine Maarouf, Pascal Jézéquel, Catherine Guette, Senescence Escape and Soluble Markers of Cancer Progression (CRCINA-ÉQUIPE 12), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, SIRIC ILIAD [Angers, Nantes], Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), This work was supported bygrants from the Ligue Contre le Cancer (comité du Maine et Loire) andfrom Comité Féminin 49 Octobre Rose., Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Oncology, Proteomics, medicine.medical_specialty, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biochemistry, Cohort Studies, 03 medical and health sciences, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Cell Line, Tumor, Granulocyte Colony-Stimulating Factor, medicine, Biomarkers, Tumor, Humans, Clinical significance, Neoplasm Invasiveness, skin and connective tissue diseases, Molecular Biology, 030304 developmental biology, 0303 health sciences, Lung, business.industry, 030302 biochemistry & molecular biology, Carcinoma, Ductal, Breast, Ductal carcinoma, medicine.disease, Prognosis, 3. Good health, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Proteome, Cohort, Biomarker (medicine), Female, business, Precancerous Conditions
Abstract: International audience; Human olfactomedin-4 (OLFM4) is a secreted protein involved in a variety of cellular functions including proliferation, differentiation, apoptosis, and cell adhesion. OLFM4 expression has been studied in several tumor types including gastric, colorectal, lung, and endometrioid cancers where it has been suggested to be an independent favorable or unfavorable prognostic marker. For breast cancer, the clinical significance of OLFM4 is still unclear. In the present study, SWATH-MS is used as a tool for the robust identification and quantification of breast tissue proteins. SWATH-MS data show that OLFM4 expression is higher in DCIS than in invasive breast cancer. In-depth analysis of the breast tumor proteome show that OLFM4 is a favorable pronostic marker. Serum OLFM4 levels in peripheral blood are also analyzed by ELISA in 825 cases, including 94 cases of healthy individuals, 61 cases of non-invasive breast tumor (DCIS) and 670 cases of breast cancer (BC). It is found that serum OLFM4 levels are significantly higher in the DCIS cohort and in the breast cancer cohort compared with the healthy controls. This result suggests that circulating OLFM4 could be an interesting biomarker of early breast cancer. Data are available via ProteomeXchange with identifier PXD014194.
Published: 2019
Full Text: View/download PDF

39. Feline Invasive Mammary Carcinomas: Prognostic Value of Histological Grading

Author: Mario Campone, Jérôme Abadie, Elie Dagher, F. Nguyen, Delphine Loussouarn, Animaux modèles pour la recherche en oncologie comparée (AMaROC), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département de Pathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Bernardo, Elizabeth, École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Oncology, medicine.medical_specialty, Prognostic factor, histological grading system, 040301 veterinary sciences, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mammary Neoplasms, Animal, Cat Diseases, survival, 0403 veterinary science, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Overall survival, Animals, Neoplasm Invasiveness, Grading (education), prognostic factor, mammary carcinoma, Neoplasm Staging, Retrospective Studies, General Veterinary, Tumor size, business.industry, Hazard ratio, Carcinoma, Retrospective cohort study, 04 agricultural and veterinary sciences, Prognosis, 3. Good health, Elston and Ellis histologic grade, 030220 oncology & carcinogenesis, Cohort, oncology, Multivariate Analysis, Cats, Female, Neoplasm Grading, business, Human breast
Abstract: International audience; Feline mammary carcinomas are highly malignant tumors usually associated with poor outcome. Nevertheless, survival times can differ significantly according to various prognostic factors. The Elston and Ellis (EE) histologic grading system, originally developed for human breast cancer, is commonly used to grade feline mammary carcinomas, although it is not really adapted for this species, hence the need of a more relevant grading system. Although few veterinary studies attempted to validate previously published results in an independent cohort, the aim of our study was to evaluate the prognostic value of different histologic grading systems in feline invasive mammary carcinomas, including the EE grading system applicable to human breast cancers and the modified and newly designed histologic grading systems recently proposed by Mills et al. Survey data and histologic features of 342 feline invasive mammary carcinomas were analyzed with respect to overall and cancer-specific survival. The histological grading system with best prognostic value was the mitotic-modified Elston and Ellis (MMEE) grading system: grade III carcinomas (P ¼ .04, hazard ratio [HR] ¼ 1.46, 95% CI, 1.01-2.11), grade II (P ¼ .03, HR ¼ 1.39, 95% CI, 1.03-1.88), and grade I carcinomas (HR ¼ 1.00, reference), with decreasing hazard ratios significantly were associated with a worse overall survival, independently from the pathologic tumor size (pT ! 20 mm: P ¼ .002, HR ¼ 1.45, 95% CI, 1.15-1.83) and positive nodal stage (P ¼ .001, HR ¼ 1.51, 95% CI, 1.18-1.94). This retrospective study validates Mills et al's proposal to adapt the thresholds for mitotic counts to better assess the histological grade of the highly proliferative mammary carcinomas encountered in the cat.
Published: 2019
Full Text: View/download PDF

40. iTRAQ‐Based Quantitative Proteomic Analysis Strengthens Transcriptomic Subtyping of Triple‐Negative Breast Cancer Tumors

Author: Catherine Guette, Hamza Lasla, Pascal Jézéquel, Wilfried Gouraud, Mario Campone, Catherine Guérin-Charbonnel, Alice Boissard, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de bioinfomique [ICO, Saint Herblain], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Unité Mixte de Génomique du Cancer [ICO, Saint Herblain] (Site René Gauducheau), UNICANCER-UNICANCER-Hôpital Guillaume-et-René-Laennec [Saint-Herblain]-Hôpital Laennec, SIRIC ILIAD [Angers, Nantes], UNICANCER, Oncologie médicale, Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Proteomics, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, Biology, Biochemistry, Medical care, Transcriptome, 03 medical and health sciences, Basal (phylogenetics), Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biomarkers, Tumor, medicine, Humans, Molecular Biology, Triple-negative breast cancer, 030304 developmental biology, 0303 health sciences, 030302 biochemistry & molecular biology, Computational Biology, Integrated approach, medicine.disease, Subtyping, Extracellular Matrix, Neoplasm Proteins, 3. Good health, Gene Expression Regulation, Neoplastic, Androgens, Female
Abstract: International audience; Heterogeneity and lack of targeted therapies represent the two main impediments to precision treatment of triple-negative breast cancer (TNBC). Therefore, molecular subtyping and identification of therapeutic pathways are required to optimize medical care. The aim of the present study is to define robust TNBC subtypes with clinical relevance by means of proteomics and transcriptomics. As a first step, unsupervised analyses are conducted in parallel on proteomics and transcriptomics data of 83 TNBC tumors. Proteomics data unsupervised analysis did not permit separation of TNBC into different subtypes, whereas transcriptomics data are able to clearly and robustly identify three subtypes: molecular apocrine (C1), basal-like immune-suppressed (C2), and basal-like immune response (C3). Supervised analysis of proteomics data are then conducted based on transcriptomics subtyping. Thirty out of 62 proteins differentially expressed between C1, C2, and C3 belonged to biological categories which characterized these TNBC clusters: luminal and androgen-regulated proteins (C1), basal, invasion, and extracellular matrix (C2), and basal and immune response (interferon pathway and immunoglobulins) (C3). Although proteomics unsupervised analysis of TNBC tumors is unsuccessful at identifying clusters, the integrated approach is promising. Identification and measurement of 30 proteins strengthen subtyping of TNBC based on robust transcriptomics unsupervised analysis.
Published: 2019
Full Text: View/download PDF

41. Regulation of senescence escape by TSP1 and CD47 following chemotherapy treatment

Author: Jean Paul Salmon, Jordan Guillon, Mario Campone, Catherine Guette, Olivier Coqueret, Eric Lelièvre, Marie Françoise Moreau, Nathalie Bonichon-Lamichhane, Véronique Verriele, Jérôme Lemonnier, Bertrand Toutain, Henry Roché, Coralie Petit, Cécile Henry, Senescence Escape and Soluble Markers of Cancer Progression (CRCINA-ÉQUIPE 12), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique Tivoli Ducos [Bordeaux], Centre Hospitalier PELTZER-LA TOURELLE [Verviers, Belgium], UNICANCER [Paris], Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Site de Recherche Intégrée sur le Cancer - SIRIC « ILIAD » [Nantes], Bernardo, Elizabeth, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Senescence, Cancer Research, Immunology, Cell, CD47 Antigen, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, Thrombospondin 1, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mice, 0302 clinical medicine, Downregulation and upregulation, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Animals, Humans, Anoikis, lcsh:QH573-671, Cellular Senescence, lcsh:Cytology, CD47, Cell Biology, Cell cycle, 3. Good health, Cell biology, Telomere, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer cell
Abstract: Senescence is a tumor-suppressive mechanism induced by telomere shortening, oncogenes, or chemotherapy treatment. Although it is clear that this suppressive pathway leads to a permanent arrest in primary cells, this might not be the case in cancer cells that have inactivated their suppressive pathways. We have recently shown that subpopulations of cells can escape chemotherapy-mediated senescence and emerge as more transformed cells that induce tumor formation, resist anoikis, and are more invasive. In this study, we characterized this emergence and showed that senescent cells favor tumor growth and metastasis, in vitro and in vivo. Senescence escape was regulated by secreted proteins produced during emergence. Among these, we identified thrombospondin-1 (TSP1), a protein produced by senescent cells that prevented senescence escape. Using SWATH quantitative proteomic analysis, we found that TSP1 can be detected in the serum of patients suffering from triple-negative breast cancer and that its low expression was associated with treatment failure. The results also indicate that senescence escape is explained by the emergence of CD47low cells that express a reduced level of CD47, the TSP1 receptor. The results show that CD47 expression is regulated by p21waf1. The cell cycle inhibitor was sufficient to maintain senescence since its downregulation in senescent cells increased cell emergence. This leads to the upregulation of Myc, which then binds to the CD47 promoter to repress its expression, allowing the generation of CD47low cells that escape the suppressive arrest. Altogether, these results uncovered a new function for TSP1 and CD47 in the control of chemotherapy-mediated senescence.
Published: 2019
Full Text: View/download PDF

42. Development of an absolute assignment predictor for triple-negative breast cancer subtyping using machine learning approaches

Author: Anne-Flore François, Catherine Guérin-Charbonnel, Hamza Lasla, Wilfried Gouraud, Théo Lecointre, Fabien Girka, Mario Campone, Bertrand Michel, Fadoua Ben Azzouz, Pascal Jézéquel, Philippe Juin, Site de Recherche Intégrée sur le Cancer [Nantes] (SIRIC), Centre hospitalier universitaire de Nantes (CHU Nantes), Imaging and Longitudinal Investigations to Ameliorate Decision-making [Nantes] (ILIAD), Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, École Centrale de Nantes (ECN), Laboratoire de Mathématiques Jean Leray (LMJL), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Bernardo, Elizabeth, Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: 0301 basic medicine, Computer science, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Health Informatics, Feature selection, Prediction models, Machine learning, computer.software_genre, 03 medical and health sciences, Variable selection, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Selection (genetic algorithm), business.industry, TNBC subtype, Computational Biology, Transcriptomics data, Precision medicine, medicine.disease, Subtyping, 3. Good health, Computer Science Applications, Random forest, 030104 developmental biology, Gradient boosting, Artificial intelligence, business, computer, Algorithms, 030217 neurology & neurosurgery, Predictive modelling
Abstract: International audience; Triple-negative breast cancer (TNBC) heterogeneity represents one of the main obstacles to precision medicine for this disease. Recent concordant transcriptomics studies have shown that TNBC could be divided into at least three subtypes with potential therapeutic implications. Although a few studies have been conducted to predict TNBC subtype using transcriptomics data, the subtyping was partially sensitive and limited by batch effect and dependence on a given dataset, which may penalize the switch to routine diagnostic testing. Therefore, we sought to build an absolute predictor (i.e., intra-patient diagnosis) based on machine learning algorithms with a limited number of probes. To that end, we started by introducing probe binary comparison for each patient (indicators). We based the predictive analysis on this transformed data. Probe selection was first involved combining both filter and wrapper methods for variable selection using cross-validation. We tested three prediction models (random forest, gradient boosting [GB], and extreme gradient boosting) using this optimal subset of indicators as inputs. Nested cross-validation consistently allowed us to choose the best model. The results showed that the fifty selected indicators highlighted the biological characteristics associated with each TNBC subtype. The GB based on this subset of indicators performs better than other models.
Published: 2021
Full Text: View/download PDF

43. Targeting of BCL-2 Family Members during Anticancer Treatment: A Necessary Compromise between Individual Cell and Ecosystemic Responses?

Author: Sophie Barillé-Nion, Philippe Juin, Steven Lohard, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, SIRIC ILIAD program supported by theFrench National Cancer Institute national (INCa), Barillé-Nion, Sophie, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: BH3 mimetics, 0301 basic medicine, Programmed cell death, [SDV]Life Sciences [q-bio], Cell, lcsh:QR1-502, Antineoplastic Agents, Apoptosis, Review, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biochemistry, lcsh:Microbiology, 03 medical and health sciences, 0302 clinical medicine, Immune system, Neoplasms, Drug Discovery, medicine, Animals, Humans, cancer, Molecular Targeted Therapy, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Caspase, biology, Bcl-2 family, Mitochondria, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, tumor ecosystem, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, MOMP, Intracellular
Abstract: International audience; The imbalance between BCL-2 homologues and pro-death counterparts frequently noted in cancer cells endows them with a cell autonomous survival advantage. To eradicate ectopic cells, inhibitors of these homologues (BH3 mimetics) were developed to trigger, during anticancer treatment, full activation of the canonical mitochondrial apoptotic pathway and related caspases. Despite efficiency in some clinical settings, these compounds do not completely fulfill their initial promise. We herein put forth that a growing body of evidence indicates that mitochondrial integrity, controlled by BCL-2 family proteins, and downstream caspases regulate other cell death modes and influence extracellular signaling by committed cells. Moreover, intercellular communications play a key role in spreading therapeutic response across cancer cell populations and in engaging an immune response. We thus advocate that BH3 mimetics administration would be more efficient in the long term if it did not induce apoptosis in all sensitive cells at the same time, but if it could instead allow (or trigger) death signal production by non-terminally committed dying cell populations. The development of such a trade-off strategy requires to unravel the effects of BH3 mimetics not only on each individual cancer cell but also on homotypic and heterotypic cell interactions in dynamic tumor ecosystems.
Published: 2020
Full Text: View/download PDF

44. Identification of paclitaxel resistance through a new statistical approach based on a random forest of perfect trees classifcation

Author: Mario Campone, Philippe Juin, Alexandre Moreau-Gaudry, Pascal Jézéquel, Daniel Antonioli, Jean-Michel Nguyen, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Oncology, Cancer Research, medicine.medical_specialty, business.industry, Paclitaxel resistance, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease, 3. Good health, Random forest, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Paclitaxel, chemistry, 030220 oncology & carcinogenesis, Internal medicine, Medicine, Identification (biology), business, Complete response, 030215 immunology
Abstract: e13513 Background: Predictors of paclitaxel sensitivity in breast cancer published ten years ago, are still pending. The authors showed that paclitaxel pathological complete response (pCR) was in one hand, encountered in aggressive breast tumor with immune response and in another hand, paclitaxel resistance in less aggressive tumor. We have developed a new analysis paradigm, mixing neurons into nodes of trees classification and news class of statistical information based on free-error trees classification. We proposed to reanalyze the Bauer et al’s dataset using this novel approach. Methods: GES22513 dataset including 14 duplicated observations and 54675 anonymized probes was analyzed. A random forest of one million trees whose nodes were composed of neurons including 15 probes, was developped. We selected probes for which a free-error classification was obtained and ranked them according to the inverse of the probability of being a confounding factor and to the inverse of the probability of interacting with another probe. We compared the sets of probes which were necessary to obtain an error-free classification between those associated with a decrease and those associated with an increase of the probability of pCR. Results: Our 15 best ranked predictors were free-error classification for all observations. This includes gene expression of TLCD2, BRCC3, CHI3L2 and PROX1. Their over-expressions were associated with an increase in the probability of pCR, and gene expression of APH1B, ARFGEF1, ARID2, BPGM, CAMK2N1, CCNY, PARM1, PHKA1, PSMD9, SUDS3 (two probes) whose over-expressions are associated with a decrease in the probability of pCR. Ten out of these probes were concordant with Bauer et al’s conclusion. Four probes ( BPGM, PHKA1, CCNY and ARFGEF1) are in contradiction with it. The limited biological information were available for TLCD2. The statistical analysis also showed that TLCD2, BBRCC3, CHI3L2 and PROX1 were altogether positively modulated by eight genes/probes ( CKS1B, ADIG, NCR3, RIN3, NIPAL1, 234422_at, DCLRE1C, SLC17A4). At the opposite, the modulation of genes associated with a decrease in the probability of pCR, was rather heterogeneous and involves many more genes. Conclusions: This preliminary work shows that our statistical approach allows a perfect classification of tumors with and without pCR. Also, it proves that the selected probes/genes are respectively associated with aggressiveness/basal and less aggressiveness/luminal phenotypes. These results need to be validated on an independent cohort.
Published: 2020
Full Text: View/download PDF

45. Proposal for a Histological Staging System of Mammary Carcinomas in Dogs and Cats. Part 2: Feline Mammary Carcinomas

Author: Florian Chocteau, Marie-Mélanie Boulay, Fanny Besnard, Germain Valeau, Delphine Loussouarn, Frédérique Nguyen, École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Animaux modèles pour la recherche en oncologie comparée (AMaROC), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de Pathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Intégré d'Oncologie Nantes/Angers, This work was supported by the French National Cancer Institute (INCa, Institut National du Cancer) with a grant for translational research (INCa-DHOS 2010, Prof. M. Campone), and by Roche Diagnostics GmbH, Germany, which provided financial and technical support for the immunohistochemical characterization of the carcinomas., Bernardo, Elizabeth, Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: medicine.medical_specialty, 040301 veterinary sciences, Lymphovascular invasion, lymphovascular invasion, cat, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, survival, 0403 veterinary science, 03 medical and health sciences, Cytokeratin, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Stage (cooking), Original Research, mammary carcinoma, pathologic tumor size, lcsh:Veterinary medicine, General Veterinary, business.industry, Hazard ratio, Myoepithelial cell, Retrospective cohort study, 04 agricultural and veterinary sciences, medicine.disease, stage, 3. Good health, 030220 oncology & carcinogenesis, lcsh:SF600-1100, Immunohistochemistry, Veterinary Science, pathologic nodal stage, prognosis, business
Abstract: International audience; Background: Feline mammary carcinomas (FMCs) are characterized by a high frequency of metastatic spread. The clinical TNM (Tumor, Node, Metastasis) system is used to describe local, regional, and distant tumor extent within the patient, but few publications confirmed its association with survival in cats with FMC. The purpose of this study was to determine if the histological staging system proposed for dogs in part 1 of this article had significant association with prognosis in cats.Materials and Methods: This retrospective study included 395 female cats with a surgically removed mammary carcinoma, with a 2-year follow-up. Invasiveness (distinction between in situ and invasive FMCs), the pathologic tumor size (pT), lymphovascular invasion (LVI), and the pathologic nodal stage (pN) defined a 5-stage system: Stage 0 (FMCs in situ), Stage I (pT1, LVI–, pN0–pNX), Stage II (pT2, LVI–, pN0–pNX), Stage IIIA (pT1, LVI+ and/or pN+), and Stage IIIB (pT2, LVI+ and/or pN+), where pT1 was ≤20 mm, pT2 was >20 mm, and pNX corresponded to unsampled draining lymph node.Results: Higher histological stages were associated with reduced disease-free interval, overall survival, and specific survival. For cancer-specific survival, by univariate analysis (p < 0.0001), median survival times and 1-year specific survival rates (1ySSR) were: stage 0 (1484 days; 1ySSR = 85%; N = 55; 14% of the cats), stage I (808 days; 1ySSR = 76%; N = 103; 26%), stage II (377 days; 1ySSR = 51%; N = 56; 14%), stage IIIA (448 days; 1ySSR = 60%; N = 83; 21%), and stage IIIB (207 days; 1ySSR = 29%; N = 98; 25%). The histological stages were also associated with specific survival by multivariate analysis (Hazard Ratio (HR) = 2.72 for stage IIIB, HR = 1.76 for stage IIIA, HR = 1.50 for stage II compared with stage I), independently of Progesterone Receptor expression (HR = 0.34 for PR+ compared with PR– FMCs) and tumor-associated inflammation (HR = 1.33 when moderate to severe compared with absent to mild).Conclusion: A same histological staging system could be applied in dogs and cats with mammary carcinoma to refine prognosis assessment. In the near future, a preoperative complete tumor clinical staging and treatment based on the published standard of care should be performed in order to better validate the histological staging system here proposed.
Published: 2019
Full Text: View/download PDF

46. Mitotic stress-induced secretome primes cancer cells to apoptosis and maximizes paclitaxel response in breast tumors when combined with BCL-xL-targeting BH3 mimetics

Author: Sophie Barillé-Nion, Philippe Juin, Steven Lohard, Université de Nantes (UN), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), CRLCC René Gauducheau, Barillé-Nion, Sophie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: BH3 mimetics, 0301 basic medicine, Cancer Research, [SDV]Life Sciences [q-bio], Priming (immunology), Bcl-xL, Biology, 03 medical and health sciences, chemistry.chemical_compound, Paracrine signalling, Antimitotic, 0302 clinical medicine, inflammatory secretome, Cytotoxic T cell, Mitosis, apoptotic priming, 3. Good health, [SDV] Life Sciences [q-bio], Author's Views, 030104 developmental biology, Paclitaxel, chemistry, Apoptosis, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, biology.protein, Molecular Medicine
Abstract: International audience; We recently identified a previously unappreciated ability of antimitotics to propagate apoptotic priming across cancer cell populations. The underlying paracrine cytotoxic signal, fueled by undead cells activating the cGAS/STING pathway, is required for in vivo antitumor response and it can be further exploited by delayed, but not synchronous, BCL-xL inhibition.
Published: 2020
Full Text: View/download PDF

47. Emerging PARP inhibitors for treating breast cancer

Author: Paule Augereau, Marie Robert, Jean-Sebastien Frenel, Mario Campone, Carole Gourmelon, Anne Patsouris, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: 0301 basic medicine, Genome instability, DNA Repair, endocrine system diseases, DNA repair, Poly ADP ribose polymerase, Antineoplastic Agents, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Poly(ADP-ribose) Polymerase Inhibitors, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, BRCA1/2, Biomarkers, Tumor, BRCAness, Humans, Medicine, Pharmacology (medical), skin and connective tissue diseases, PARP inhibitors, Pharmacology, business.industry, medicine.disease, 3. Good health, 030104 developmental biology, Drug Resistance, Neoplasm, Drug Design, 030220 oncology & carcinogenesis, Mutation, Cancer research, Female, business, DNA Damage
Abstract: International audience; Some breast cancers harbor defects in DNA repair pathways, including BRCA1 and BRCA2 mutations, leading to a genomic instability. Compromised DNA-damage repair response is found in 11 to 42% of triple negative breast cancers, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors are a promising strategy in breast cancer exploiting Homologous Deficient Recombination deficiency (HRD) by a synthetic lethal approach. Several PARP inhibitors have currently reached early phase trials with studies on going in the adjuvant, neoadjuvant and metastatic setting. Area covered: Here, we review completed and ongoing trials with PARP inhibitors as well as their mechanisms of activity and acquired resistance. Expert opinion: PARP inhibitors show promising results in breast cancer. However, several issues are raised including the identification of biomarkers to predict treatment response and strategies to counteract emerging resistance.
Published: 2018
Full Text: View/download PDF

48. Escape from mitotic arrest mediates long term mito-priming of cancer cells by cell autonomous and non-cell autonomous mechanisms

Author: Barillé-Nion, Sophie, Lohard, Steven, Juin, Philippe, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Barillé-Nion, Sophie
Subjects: [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2018

49. The oncogenic tyrosine kinase Lyn impairs the pro-apoptotic function of Bim

Author: Pascal Colosetti, Emma Proïcs, Frederic Luciano, Jean-Ehrland Ricci, Guillaume Robert, Lazaro Emilio Aira, Fabien Gautier, Laurie Signetti, Sandrine Marchetti, Philippe Juin, Parvati Gamas, Elodie Villa, Sandrine Obba, Béatrice Bailly-Maitre, Arnaud Jacquel, Patrick Auberger, Stress Adaptation and Tumor Escape in breast cancer - SATE ( CRCINA - Département ONCO - Equipe 8 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Bernardo, Elizabeth, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: 0301 basic medicine, Cancer Research, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, environment and public health, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, LYN, hemic and lymphatic diseases, Genetics, Animals, Humans, Tyrosine, Molecular Biology, Cells, Cultured, Bcl-2-Like Protein 11, biology, Cytochrome c, Tyrosine phosphorylation, hemic and immune systems, Oncogenes, Mitochondria, Cell biology, enzymes and coenzymes (carbohydrates), Cell Transformation, Neoplastic, HEK293 Cells, src-Family Kinases, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, Phosphorylation, biological phenomena, cell phenomena, and immunity, K562 Cells, Tyrosine kinase, HeLa Cells, Signal Transduction
Abstract: International audience; Phosphorylation of Ser/Thr residues is a well-established modulating mechanism of the pro-apoptotic function of the BH3-only protein Bim. However, nothing is known about the putative tyrosine of this Bcl-2 family member and its potential impact on Bim function and subsequent Bax/Bak-mediated cytochrome c release and apoptosis. As we have previously shown that the tyrosine kinase Lyn could behave as an anti-apoptic molecule, we investigated whether this Src family member could directly regulate the pro-apoptotic function of Bim. In the present study, we show that Bim is phosphorylated onto tyrosine residues 92 and 161 by Lin, which results is an inhibition of its pro-apoptotic function. Mechanistically, we show that Lyn-dependent tyrosine phosphorylation of Bim increases its interaction with anti-apoptic members such as Bcl-xL, therefore limiting mitochondrial outer membrane permeabilization and subsequent apoptosis. Collectively, our data uncover one molecular mechanism through which the oncogenic tyrosine kinase Lyn negatively regulates the mitochondrial apoptic pathway, which may contribute to the transformation and/or the chemotherapeutic resistance of cancer cells.
Published: 2018
Full Text: View/download PDF

50. Targeting PUMA/Bcl-xL interaction by new specific compounds to unleash apoptotic process in cancer cells

Author: Appala Venkata Ramana Murthy, Nicolas Levoin, Sophie Barillé-Nion, Philippe Juin, A. K. D. Bhavani, René Grée, Fabien Gautier, Nangunoori Sampath Kumar, Vennu Narendar, Pasula Aparna, Paul Mosset, Jawaharlal Nehru University (JNU), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Bioprojet-Biotech, Ligue contre le Cancer, Conseil Interrégional Grand Ouest, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)
Subjects: Models, Molecular, Protein-protein interactions, bcl-X Protein, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bcl-xL, Apoptosis, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, Protein–protein interaction, 03 medical and health sciences, Apoptotic Process, PUMA, Puma, Neoplasms, Proto-Oncogene Proteins, Drug Discovery, medicine, Animals, Humans, Protein Interaction Domains and Motifs, ComputingMilieux_MISCELLANEOUS, Cancer, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, 010405 organic chemistry, Chemistry, Organic Chemistry, General Medicine, medicine.disease, biology.organism_classification, Small molecule, 0104 chemical sciences, Interaction studies, Cancer cell, biology.protein, Cancer research, BRET, Molecular modelling, Apoptosis Regulatory Proteins
Abstract: We describe the first examples of small molecules able to disrupt the nanomolar interaction between the pro-apoptotic protein PUMA and its anti-apoptotic counterpart BcL-xL in malignant cells. Based on molecular modelling studies, we propose a rationale to this result, through a new "bottle-opener"-type strategy which could be of general use in the area of protein-protein interaction studies.
Published: 2018
Full Text: View/download PDF

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Journal

Database

Publisher

61 results on '"Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8)"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources