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1,684 results on '"Institut Curie"'

1. Evolution of synchronous female bilateral breast cancers and response to treatment

Author

Anne-Sophie Hamy, Judith Abécassis, Keltouma Driouch, Lauren Darrigues, Mathias Vandenbogaert, Cecile Laurent, Francois Zaccarini, Benjamin Sadacca, Myriam Delomenie, Enora Laas, Odette Mariani, Thanh Lam, Beatriz Grandal, Marick Laé, Ivan Bieche, Sophie Vacher, Jean-Yves Pierga, Etienne Brain, Celine Vallot, Judicael Hotton, Wilfrid Richer, Dario Rocha, Zakia Tariq, Veronique Becette, Didier Meseure, Laetitia Lesage, Anne Vincent-Salomon, Natalie Filmann, Jenny Furlanetto, Sibylle Loibl, Elise Dumas, Joshua J. Waterfall, Fabien Reyal, Residual Tumor & Response to Treatment Laboratory [Paris] (RT2Lab), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Modèles et inférence pour les données de Neuroimagerie (MIND), IFR49 - Neurospin - CEA, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Méthodes computationnelles et mathématiques pour comprendre la société et la santé à partir de données (SODA), Inria Saclay - Ile de France, Département de chirurgie, Département de Recherche Translationnelle, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement de chirurgie [Institut Curie], Geneva University Hospitals and Geneva University, Département de Pathologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Jean Godinot [Reims], UNICANCER, and German Breast Group (GBG)

Subjects
[SDV]Life Sciences [q-bio], General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract

Synchronous bilateral breast cancer (sBBC) occurs after both breasts have been affected by the same germline genetics and environmental exposures. Little evidence exists regarding immune infiltration and response to treatment in sBBCs. Here we show that the impact of the subtype of breast cancer on levels of tumor infiltrating lymphocytes (TILs, n = 277) and on pathologic complete response (pCR) rates (n = 140) differed according to the concordant or discordant subtype of breast cancer of the contralateral tumor: luminal breast tumors with a discordant contralateral tumor had higher TIL levels and higher pCR rates than those with a concordant contralateral tumor. Tumor sequencing revealed that left and right tumors (n = 20) were independent regarding somatic mutations, copy number alterations and clonal phylogeny, whereas primary tumor and residual disease were closely related both from the somatic mutation and from the transcriptomic point of view. Our study indicates that tumor-intrinsic characteristics may have a role in the association of tumor immunity and pCR and demonstrates that the characteristics of the contralateral tumor are also associated with immune infiltration and response to treatment.

Published
2023

2. Structural basis of CHMP2A–CHMP3 ESCRT-III polymer assembly and membrane cleavage

Author

Kimi Azad, Delphine Guilligay, Cecile Boscheron, Sourav Maity, Nicola De Franceschi, Guidenn Sulbaran, Gregory Effantin, Haiyan Wang, Jean-Philippe Kleman, Patricia Bassereau, Guy Schoehn, Wouter H. Roos, Ambroise Desfosses, Winfried Weissenhorn, Molecular Biophysics, Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Zernike Institute for Advanced Materials, University of Groningen [Groningen], Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ANR-14-CE09-0003,ESCRTfission,Mécanique de fission membranaire induite par ESCRT-III(2014), ANR-19-CE11-0002,Neck4Fission,Coupure des cous membranaires par les ESCRT-III(2019), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)

Subjects
MESH: Protein Transport, MESH: Humans, Structural Biology, [SDV]Life Sciences [q-bio], MESH: Carrier Proteins, Molecular Biology, MESH: Endosomal Sorting Complexes Required for Transport, MESH: Polymers
Abstract

International audience; The endosomal sorting complex required for transport (ESCRT) is a highly conserved protein machinery that drives a divers set of physiological and pathological membrane remodeling processes. However, the structural basis of ESCRT-III polymers stabilizing, constricting and cleaving negatively curved membranes is yet unknown. Here we present cryo-EM structures of membrane-coated CHMP2A-CHMP3 filaments from Homo sapiens of two different diameters at 3.3 and 3.6 Å resolution. The structures reveal helical filaments assembled by CHMP2A-CHMP3 heterodimers in the open ESCRT-III conformation, which generates a partially positive charged membrane interaction surface, positions short N-terminal motifs for membrane interaction and the C-terminal VPS4 target sequence toward the tube interior. Inter-filament interactions are electrostatic, which may facilitate filament sliding upon VPS4-mediated polymer remodeling. Fluorescence microscopy as well as high-speed atomic force microscopy imaging corroborate that VPS4 can constrict and cleave CHMP2A-CHMP3 membrane tubes. We therefore conclude that CHMP2A-CHMP3-VPS4 act as a minimal membrane fission machinery.

Published
2023

3. ETV3 and ETV6 enable monocyte differentiation into dendritic cells by repressing macrophage fate commitment

Author

Javiera Villar, Adeline Cros, Alba De Juan, Lamine Alaoui, Pierre-Emmanuel Bonte, Colleen M. Lau, Ioanna Tiniakou, Boris Reizis, Elodie Segura, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), New York University School of Medicine (NYU Grossman School of Medicine), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-10-LABX-0043,BRAIN,Bordeaux Region Aquitaine Initiative for Neuroscience(2010), ANR-17-CE15-0011,MonoDiff,Régulation moléculaire de la différenciation des monocytes : des mécanismes aux cibles thérapeutiques(2017), European Project: 666003,H2020,H2020-MSCA-COFUND-2014,IC-3i-PhD(2016), Segura, Elodie, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Bordeaux Region Aquitaine Initiative for Neuroscience - - BRAIN2010 - ANR-10-LABX-0043 - LABX - VALID, Régulation moléculaire de la différenciation des monocytes : des mécanismes aux cibles thérapeutiques - - MonoDiff2017 - ANR-17-CE15-0011 - AAPG2017 - VALID, and Institut Curie 3-i PhD Program - IC-3i-PhD - - H20202016-09-01 - 2021-09-01 - 666003 - VALID

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Immunology, Immunology and Allergy
Abstract

In inflamed tissues, monocytes differentiate into macrophages (mo-Macs) or dendritic cells (mo-DCs). In chronic nonresolving inflammation, mo-DCs are major drivers of pathogenic events. Manipulating monocyte differentiation would therefore be an attractive therapeutic strategy. However, how the balance of mo-DC versus mo-Mac fate commitment is regulated is not clear. In the present study, we show that the transcriptional repressors ETV3 and ETV6 control human monocyte differentiation into mo-DCs. ETV3 and ETV6 inhibit interferon (IFN)-stimulated genes; however, their action on monocyte differentiation is independent of IFN signaling. Instead, we find that ETV3 and ETV6 directly repress mo-Mac development by controlling MAFB expression. Mice deficient for Etv6 in monocytes have spontaneous expression of IFN-stimulated genes, confirming that Etv6 regulates IFN responses in vivo. Furthermore, these mice have impaired mo-DC differentiation during inflammation and reduced pathology in an experimental autoimmune encephalomyelitis model. These findings provide information about the molecular control of monocyte fate decision and identify ETV6 as a therapeutic target to redirect monocyte differentiation in inflammatory disorders.

Published
2022

4. Mechanical stress driven by rigidity sensing governs epithelial stability

Author

Surabhi Sonam, Lakshmi Balasubramaniam, Shao-Zhen Lin, Ying Ming Yow Ivan, Irina Pi-Jaumà, Cecile Jebane, Marc Karnat, Yusuke Toyama, Philippe Marcq, Jacques Prost, René-Marc Mège, Jean-François Rupprecht, Benoît Ladoux, Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Physique Théorique - UMR 7332 (CPT), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), CPT - E5 Physique statistique et systèmes complexes, Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Mechanobiology Institute [Singapore] (MBI), National University of Singapore (NUS), Sorbonne Université - Faculté de Physique (UFR 925), Sorbonne Université (SU), Procédés et Mécanique des Matériaux (PMM), Institut de Recherche en Génie Civil et Mécanique (GeM), Centre National de la Recherche Scientifique (CNRS)-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)-Nantes Université - Institut Universitaire de Technologie Saint-Nazaire (Nantes Univ - IUT Saint-Nazaire), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - Ecole Polytechnique de l'Université de Nantes (Nantes Univ - EPUN), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Nantes (Nantes Univ - ECN), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), ANR-16-CONV-0001,CENTURI,CenTuri : Centre Turing des Systèmes vivants(2016), ANR-17-CE13-0012,MecanoAdipo,Mécanotransduction des cellules souches adipeuses et applications pour l'ingénierie tissulaire(2017), ANR-20-CE30-0023,COVFEFE,Hydrodynamique Covariante, Fluctuante et Active des Ecoulements Epithéliaux(2020), ANR-19-CE13-0016,MyoFuse,Contrôle génétique et mécanique de la fusion des myoblastes(2019), Biophysique (BIOPHYSIQUE), Institut Lumière Matière [Villeurbanne] (ILM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), and Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[PHYS]Physics [physics], [SDV]Life Sciences [q-bio], General Physics and Astronomy, [SDV.BC]Life Sciences [q-bio]/Cellular Biology
Abstract

Epithelia act as a barrier against environmental stress and abrasion and in vivo they are continuously exposed to environments of various mechanical properties. The impact of this environment on epithelial integrity remains elusive. By culturing epithelial cells on 2D hydrogels, we observe a loss of epithelial monolayer integrity through spontaneous hole formation when grown on soft substrates. Substrate stiffness triggers an unanticipated mechanical switch of epithelial monolayers from tensile on soft to compressive on stiff substrates. Through active nematic modelling, we find unique patterns of cell shape texture called nematic topological defects that underpin large isotropic stress fluctuations at certain locations thereby triggering mechanical failure of the monolayer and hole opening. Our results show that substrate stiffness provides feedback on monolayer mechanical state and that topological defects can trigger stochastic mechanical failure, with potential application towards a mechanistic understanding of compromised epithelial integrity in bacterial infection, tumor progression and morphogenesis.

Published
2022

5. Contribution of endocrine therapy in oestrogen receptor-positive pT1a-b breast cancer: Results of a retrospective study

Author

Gilles Houvenaeghel, Alexandre de Nonneville, Monique Cohen, Jean-Marc Classe, Fabien Reyal, Chafika Mazouni, Christelle Faure, Alejandra Martinez, Marie-Pierre Chauvet, Emile Daraï, Charles Coutant, Pierre-Emmanuel Colombo, Pierre Gimbergues, Anne-Sophie Azuar, Roman Rouzier, Christine Tunon de Lara, Patrice Crochet, Sandrine Rua, Anthony Gonçalves, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Chirurgie Oncologique [Institut Paoli-Calmettes, Marseille], Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Département de chirurgie, Institut Curie [Paris], CRLCC Jean Godinot, Residual Tumor & Response to Treatment Laboratory [Paris] (RT2Lab), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Institut du Cancer de Montpellier (ICM), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Hopital de Grasse, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'oncologie chirurgicale, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Obstetrics and Gynecology, Assistance Publique H^opitaux de Marseille, La Conception Hospital, 13005 Marseille, Aix Marseille University, France, and Aix Marseille Université (AMU)

Subjects
Cancer Research, Receptors, Estrogen, Oncology, Chemotherapy, Adjuvant, Receptor, ErbB-2, [SDV]Life Sciences [q-bio], Humans, Female, Breast Neoplasms, Disease-Free Survival, Retrospective Studies
Abstract

Introduction: Few data have been reported regarding endocrine therapy (ET) in patients with small pT1a-b ER-postive breast cancer (BC). Thus, we conducted a study to detect possible survival improvements due to ET in such patients. Methods: Our retrospective observational study included 5545 patients with pT1a-b ERpositive BC treated in 15 French centres, excluding patients with HER2-positive status, neoadjuvant chemotherapy, ER-negative status, unknown pN status or in situ BC. We estimated disease-free survival (DFS), recurrence-free survival (RFS) and overall survival (OS) via univariate analysis and multivariate Cox regression. Results: Most patients (80.3%: 4453) received ET and-when compared to those without ET -experienced increases of 2.5% and 3.3% in DFS and 1.9% and 4.3% in RFS after 5 and 7 years of follow-up, respectively, with little difference in OS. In Cox regression analysis, no ET was significantly associated with decreased DFS (hazard ratio, HR = 1.275, p = 0.047, 95% CI[1.003-1.620]) but not OS or RFS in all patients, while in 2363 patients with pT1ab ER-positive grade 2-3 BC, no ET was significantly associated with decreased DFS (HR = 1.502, p = 0.049, 95% CI[1.001-2.252]), but not OS (HR = 1.361, p = 0.272). ET omission was not significantly associated with decreased survival in 3047 patients with pT1a-b ER-positive grade 1 BC. Conclusion: Our results indicate that while ET provided a beneficial impact on survival to patients with pT1a-bN0 ER-positive BC-and especially in those with grade 2-3 tumours-no such impact was observed in grade 1 tumours. Consequently, ET should be discussed with these patients, particularly in those with pT1a grade 1 tumours. 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Published
2022

6. Dynamics of Long-Term Patient-Reported Quality of Life and Health Behaviors After Adjuvant Breast Cancer Chemotherapy

Author

Antonio Di Meglio, Julie Havas, Arnauld S. Gbenou, Elise Martin, Mayssam El-Mouhebb, Barbara Pistilli, Gwenn Menvielle, Agnes Dumas, Sibille Everhard, Anne-Laure Martin, Paul H. Cottu, Florence Lerebours, Charles Coutant, Anne Lesur, Olivier Tredan, Patrick Soulie, Laurence Vanlemmens, Florence Joly, Suzette Delaloge, Patricia A. Ganz, Fabrice André, Ann H. Partridge, Lee W. Jones, Stefan Michiels, Ines Vaz-Luis, Institut Gustave Roussy (IGR), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), UNICANCER, Institut Curie [Paris], Institut Curie - Saint Cloud (ICSC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Centre Léon Bérard [Lyon], CRLCC Paul Papin, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Département de médecine oncologique [Gustave Roussy], University of California [Los Angeles] (UCLA), University of California (UC), Dana-Farber Cancer Institute [Boston], Memorial Sloane Kettering Cancer Center [New York], Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, and ANR-18-IBHU-0002,PRISM,PRecISion Medicine Institute in oncology(2018)

Subjects
Cancer Research, Prevention, [SDV]Life Sciences [q-bio], Health Behavior, Clinical Sciences, Oncology and Carcinogenesis, Breast Neoplasms, Oncology, Chemotherapy, Adjuvant, Clinical Research, Breast Cancer, Behavioral and Social Science, Quality of Life, Humans, Chemotherapy, Female, Patient Reported Outcome Measures, Oncology & Carcinogenesis, Adjuvant, Cancer
Abstract

PURPOSE We aimed to characterize long-term quality of life (QOL) trajectories among patients with breast cancer treated with adjuvant chemotherapy and to identify related patterns of health behaviors. METHODS Female stage I-III breast cancer patients receiving chemotherapy in CANTO (CANcer TOxicity; ClinicalTrials.gov identifier: NCT01993498 ) were included. Trajectories of QOL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–C30 Summary Score) and associations with trajectory group membership were identified by iterative estimations of group-based trajectory models and multivariable multinomial logistic regression, respectively. RESULTS Four trajectory groups were identified (N = 4,131): excellent (51.7%), very good (31.7%), deteriorating (10.0%), and poor (6.6%) QOL. The deteriorating trajectory group reported fairly good baseline QOL (mean [95% CI], 78.3/100 [76.2 to 80.5]), which significantly worsened at year-1 (58.1/100 [56.4 to 59.9]) and never recovered to pretreatment values through year-4 (61.1/100 [59.0 to 63.3]) postdiagnosis. Healthy behaviors were associated with better performing trajectory groups. Obesity (adjusted odds ratio [aOR] v lean, 1.51 [95% CI, 1.28 to 1.79]; P < .0001) and current smoking (aOR v never, 1.52 [95% CI, 1.27 to 1.82]; P < .0001) at diagnosis were associated with membership to the deteriorating group, which was also characterized by a higher prevalence of patients with excess body weight and insufficient physical activity through year-4 and by frequent exposure to tobacco smoking during chemotherapy. Additional factors associated with membership to the deteriorating group included younger age (aOR, 1-year decrement 1.01 [95% CI, 1.01 to 1.02]; P = .043), comorbidities (aOR v no, 1.22 [95% CI, 1.06 to 1.40]; P = .005), lower income (aOR v wealthier households, 1.21 [95% CI, 1.07 to 1.37]; P = .002), and endocrine therapy (aOR v no, 1.14 [95% CI, 1.01 to 1.30]; P = .047). CONCLUSION This latent-class analysis identified some patients with upfront poor QOL and a high-risk cluster with severe, persistent postchemotherapy QOL deterioration. Screening relevant patient-level characteristics may inform tailored interventions to mitigate the detrimental impact of chemotherapy and preserve QOL, including early addressal of behavioral concerns and provision of healthy lifestyle support programs.

Published
2022

7. Cell fragmentation in mouse preimplantation embryos induced by ectopic activation of the polar body extrusion pathway

Author

Pelzer, Diane, de Plater, Ludmilla, Bradbury, Peta, Eichmuller, Adrien, Bourdais, Anne, Halet, Guillaume, Maître, Jean-Léon, Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), 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 ), Research in the lab of J-LM is supported by the Institut Curie, the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé Et de la Recherche Médicale (INSERM), and is funded by grants from the ATIP–Avenir Program, the Fondation Schlumberger pour l'Éducation et la Recherche via the Fondation pour la Recherche Médicale, the European Research Council Starting Grant ERC-2017-StG 757557, the Agence Nationale de la Recherche (ANR-21-CE13-0010-02), the European Molecular Biology Organization Young Investigator program (EMBO YIP), the INSERM transversal program Human Development Cell Atlas (HuDeCA), Paris Sciences Lettres (PSL) QLife (17-CONV-0005) grant and Labex DEEP (ANR-11-LABX-0044) which are part of the IDEX PSL (ANR-10-IDEX-0001-02)., ANR-21-CE13-0010,MyoCortex,Régulation du cortex de l'actine par myosine de classe I Myo1C(2021), ANR-11-LABX-0044,DEEP,Développement, Epigénèse, Epigénétique et potentiel de vie(2011), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-17-CONV-0005,Q-LIFE,Institut Q-LIFE(2017), and European Project: 757557,ERC-2017-STG ,MECHABLASTO(2018)

Subjects
mitosis, [SDV]Life Sciences [q-bio], preimplantation development, meiosis, morphogenesis, cytoskeleton
Abstract

International audience; Cell fragmentation is commonly observed in human preimplantation embryos and is associated with poor prognosis during assisted reproductive technology (ART) procedures. However, the mechanisms leading to cell fragmentation remain largely unknown. Here, light sheet microscopy imaging of mouse embryos reveals that inefficient chromosome separation due to spindle defects, caused by dysfunctional molecular motors Myo1c or dynein, leads to fragmentation during mitosis. Extended exposure of the cell cortex to chromosomes locally triggers actomyosin contractility and pinches off cell fragments. This process is reminiscent of meiosis, during which small GTPase-mediated signals from chromosomes coordinate polar body extrusion (PBE) by actomyosin contraction. By interfering with the signals driving PBE, we find that this meiotic signaling pathway remains active during cleavage stages and is both required and sufficient to trigger fragmentation. Together, we find that fragmentation happens in mitosis after ectopic activation of actomyosin contractility by signals emanating from DNA, similar to those observed during meiosis. Our study uncovers the mechanisms underlying fragmentation in preimplantation embryos and, more generally, offers insight into the regulation of mitosis during the maternal-zygotic transition.

Published
2023

8. Filopodia-like protrusions of adjacent somatic cells shape the developmental potential of oocytes

Author

Flora Crozet, Gaëlle Letort, Rose Bulteau, Christelle Da Silva, Adrien Eichmuller, Anna Francesca Tortorelli, Joséphine Blévinal, Morgane Belle, Julien Dumont, Tristan Piolot, Aurélien Dauphin, Fanny Coulpier, Alain Chédotal, Jean-Léon Maître, Marie-Hélène Verlhac, Hugh J Clarke, Marie-Emilie Terret, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-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), Centre de recherche de l'Institut Curie [Paris], Institut Curie [Paris], Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Biologie du système neuromusculaire - Biology of the neuromuscular system [Maisons-Alfort] (BNMS - Team 10), École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), The STED microscopy was performed at the Orion Platform (member of France-Bioimaging ANR-10-INBS-XX) of the Center for Interdisciplinary Research in Biology (UMR7241/U1050) of Collège de France. The OMX microscopy was performed at the Cell and Tissue Imaging Platform-PICT-IBiSA of the Genetics and Developmental Biology Department (UMR3215/U934) of Institut Curie. This work was supported by the Fondation pour la Recherche Médicale (FRM Label EQU201903007796 to M-H Verlhac), by the Agence Nationale de la Recherche (ANR-18-CE13 to M-H Verlhac and Auguste Genovesio, IBENS/ENS, ANR-16-CE13 to M-E Terret), and by the France Canada Research Fund (FCRF 2017 to M-E Terret and Hugh J Clarke, McGill University). F Crozet obtained a grant from the Fondation pour la Recherche Médicale for her fourth PhD year (FDT202001010906). This work has received support from the Fondation Bettencourt Schueller.., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-10-LABX-0054,MEMOLIFE,Memory in living systems: an integrated approach(2010), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), and European Project: 250367,EC:FP7:ERC,ERC-2009-AdG,EPIGENETIX(2010)

Subjects
Ecology, Health, Toxicology and Mutagenesis, [SDV]Life Sciences [q-bio], Plant Science, Biochemistry, Genetics and Molecular Biology (miscellaneous)
Abstract

The oocyte must grow and mature before fertilization, thanks to a close dialogue with the somatic cells that surround it. Part of this communication is through filopodia-like protrusions, called transzonal projections (TZPs), sent by the somatic cells to the oocyte membrane. To investigate the contribution of TZPs to oocyte quality, we impaired their structure by generating a full knockout mouse of the TZP structural component myosin-X (MYO10). Using spinning disk and super-resolution microscopy combined with a machine-learning approach to phenotype oocyte morphology, we show that the lack ofMyo10decreases TZP density during oocyte growth. Reduction in TZPs does not prevent oocyte growth but impairs oocyte-matrix integrity. Importantly, we reveal by transcriptomic analysis that gene expression is altered in TZP-deprived oocytes and that oocyte maturation and subsequent early embryonic development are partially affected, effectively reducing mouse fertility. We propose that TZPs play a role in the structural integrity of the germline–somatic complex, which is essential for regulating gene expression in the oocyte and thus its developmental potential.

Published
2023

9. H3K27me3 conditions chemotolerance in triple-negative breast cancer

Author

Justine Marsolier, Pacôme Prompsy, Adeline Durand, Anne-Marie Lyne, Camille Landragin, Amandine Trouchet, Sabrina Tenreira Bento, Almut Eisele, Sophie Foulon, Léa Baudre, Kevin Grosselin, Mylène Bohec, Sylvain Baulande, Ahmed Dahmani, Laura Sourd, Eric Letouzé, Anne-Vincent Salomon, Elisabetta Marangoni, Leïla Perié, Céline Vallot, Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de Recherche Translationnelle, Institut Curie [Paris], Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Chimie-Biologie-Innovation (UMR 8231) (CBI), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), HiFiBiO Therapeutics SAS [Paris], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Plateforme de Séquençage ADN haut débit [Institut Curie] (NGS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the ATIP Avenir program, by Plan Cancer, by the SiRIC-Curie program SiRIC Grants #INCa-DGOS-4654 and #INCa-DGOS-Inserm_12554, and by a starting ERC grant from the H2020 program #948528-ChromTrace (to CV), and by the Fondation de France #00107944 (to JM). The work was supported by an ATIP-Avenir grant from CNRS and Bettencourt-Schueller Foundation, by a starting ERC grant from the H2020 program #758170-Microbar (to LP). And by the SiRIC-Curie program SiRIC Grant #INCa-DGOS- 4654., ANR-11-LABX-0038,CelTisPhyBio,Des cellules aux tissus: au croisement de la Physique et de la Biologie(2011), ANR-10-EQPX-0003,ICGex,Equipement de biologie intégrative du cancer pour une médecine personnalisée(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Perié, Leïla, Des cellules aux tissus: au croisement de la Physique et de la Biologie - - CelTisPhyBio2011 - ANR-11-LABX-0038 - LABX - VALID, Equipements d'excellence - Equipement de biologie intégrative du cancer pour une médecine personnalisée - - ICGex2010 - ANR-10-EQPX-0003 - EQPX - VALID, and Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID

Subjects
Histones, [SDV] Life Sciences [q-bio], Breast cancer, Drug Resistance, Neoplasm, Lysine, [SDV]Life Sciences [q-bio], Genetics, Humans, Triple Negative Breast Neoplasms, Epigenetics, Neoplasm Recurrence, Local, Methylation
Abstract

International audience; The persistence of cancer cells resistant to therapy remains a major clinical challenge. In triple-negative breast cancer, resistance to chemotherapy results in the highest recurrence risk among breast cancer subtypes. The drug-tolerant state seems largely defined by nongenetic features, but the underlying mechanisms are poorly understood. Here, by monitoring epigenomes, transcriptomes and lineages with single-cell resolution, we show that the repressive histone mark H3K27me3 (trimethylation of histone H3 at lysine 27) regulates cell fate at the onset of chemotherapy. We report that a persister expression program is primed with both H3K4me3 (trimethylation of histone H3 at lysine 4) and H3K27me3 in unchallenged cells, with H3K27me3 being the lock to its transcriptional activation. We further demonstrate that depleting H3K27me3 enhances the potential of cancer cells to tolerate chemotherapy. Conversely, preventing H3K27me3 demethylation simultaneously to chemotherapy inhibits the transition to a drug-tolerant state, and delays tumor recurrence in vivo. Our results highlight how chromatin landscapes shape the potential of cancer cells to respond to initial therapy.

Published
2022

10. RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia

Author

Justine Decroocq, Rudy Birsen, Camille Montersino, Prasad Chaskar, Jordi Mano, Laury Poulain, Chloe Friedrich, Anne-Sophie Alary, Helene Guermouche, Ambrine Sahal, Guillemette Fouquet, Mathilde Gotanègre, Federico Simonetta, Sarah Mouche, Pierre Gestraud, Auriane Lescure, Elaine Del Nery, Claudie Bosc, Adrien Grenier, Fetta Mazed, Johanna Mondesir, Nicolas Chapuis, Liza Ho, Aicha Boughalem, Marc Lelorc’h, Camille Gobeaux, Michaela Fontenay, Christian Recher, Norbert Vey, Arnaud Guillé, Daniel Birnbaum, Olivier Hermine, Isabelle Radford-Weiss, Petros Tsantoulis, Yves Collette, Rémy Castellano, Jean-Emmanuel Sarry, Eric Pasmant, Didier Bouscary, Olivier Kosmider, Jerome Tamburini, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Université Paris Cité (UPCité), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Sud Francilien, Laboratorio d'Informatica Musicale (LIM), Università degli Studi di Milano = University of Milan (UNIMI), Institut Curie [Paris], Centre de Bioinformatique (CBIO), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Translational Research Department, Institut Curie, BioImaging Cell and Tissue Core Facility (PICT-IBiSA), Université de Genève = University of Geneva (UNIGE), Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Laboratoire CERBA [Saint Ouen l'Aumône], Département d’Oncologie Médicale [IPC, Marseille], Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Cancer Research and Personalized Medicine - CARPEM [Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP]

Subjects
Mitogen-Activated Protein Kinase Kinases, Cancer Research, [SDV]Life Sciences [q-bio], Hematology, Proto-Oncogene Proteins p21(ras), Leukemia, Myeloid, Acute, Mice, Oxidative Stress, fms-Like Tyrosine Kinase 3, Oncology, hemic and lymphatic diseases, Mutation, Animals, Humans, Synthetic Lethal Mutations, neoplasms
Abstract

Despite recent advances in acute myeloid leukemia (AML) molecular characterization and targeted therapies, a majority of AML cases still lack therapeutically actionable targets. In 127 AML cases with unmet therapeutic needs, as defined by the exclusion of ELN favorable cases and of FLT3-ITD mutations, we identified 51 (40%) cases with alterations in RAS pathway genes (RAS+, mostly NF1, NRAS, KRAS, and PTPN11 genes). In 79 homogeneously treated AML patients from this cohort, RAS+ status were associated with higher white blood cell count, higher LDH, and reduced survival. In AML models of oncogenic addiction to RAS-MEK signaling, the MEK inhibitor trametinib demonstrated antileukemic activity in vitro and in vivo. However, the efficacy of trametinib was heterogeneous in ex vivo cultures of primary RAS+ AML patient specimens. From repurposing drug screens in RAS-activated AML cells, we identified pyrvinium pamoate, an anti-helminthic agent efficiently inhibiting the growth of RAS+ primary AML cells ex vivo, preferentially in trametinib-resistant PTPN11- or KRAS-mutated samples. Metabolic and genetic complementarity between trametinib and pyrvinium pamoate translated into anti-AML synergy in vitro. Moreover, this combination inhibited the propagation of RA+ AML cells in vivo in mice, indicating a potential for future clinical development of this strategy in AML.

Published
2022

11. The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies

Author

Pablo Berlanga, Gaelle Pierron, Ludovic Lacroix, Mathieu Chicard, Tiphaine Adam de Beaumais, Antonin Marchais, Anne C. Harttrampf, Yasmine Iddir, Alicia Larive, Aroa Soriano Fernandez, Imene Hezam, Cecile Chevassus, Virginie Bernard, Sophie Cotteret, Jean-Yves Scoazec, Arnaud Gauthier, Samuel Abbou, Nadege Corradini, Nicolas André, Isabelle Aerts, Estelle Thebaud, Michela Casanova, Cormac Owens, Raquel Hladun-Alvaro, Stefan Michiels, Olivier Delattre, Gilles Vassal, Gudrun Schleiermacher, Birgit Geoerger, Institut Català de la Salut, [Berlanga P] Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Pierron G] Unité de Génétique Somatique, Service de Génétique, Hospital Group, Institut Curie, Paris, France. [Lacroix L] Department of Pathology and Laboratory Medicine, Translational Research Laboratory and Biobank, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Chicard M] INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Research Center, PSL Research University, Institut Curie, Paris, France. [Adam de Beaumais T] Clinical Research Direction, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Marchais A] INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Soriano Fernandez A] Grup de Recerca Translacional en Càncer en la Infància i l’Adolescència, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Hladun-Alvaro R] Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Servei d’Oncologia i Hematologia Pediàtriques, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Institut Gustave Roussy (IGR), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Curie [Paris], Department of Medical Oncology, Département de médecine oncologique [Gustave Roussy], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de Bioinformatique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de Recherche et de Documentation sur l'Océanie (CREDO), École des hautes études en sciences sociales (EHESS)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique [Châtenay-Malabry] (LabEx LERMIT), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de biologie et pathologie médicales [Gustave Roussy], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Centre Léon Bérard [Lyon], Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Immunologie des tumeurs et immunothérapie (UMR 1015), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS)

Subjects
neoplasias::procesos neoplásicos::recurrencia neoplásica local [ENFERMEDADES], Pediatria, Adolescent, [SDV]Life Sciences [q-bio], Carcinoma, High-Throughput Nucleotide Sequencing, Neoplasms [DISEASES], neoplasias [ENFERMEDADES], Càncer - Recaiguda, terapéutica::medicina de precisión [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Oncology, Mutation, Biomarkers, Tumor, Neoplasms::Neoplastic Processes::Neoplasm Recurrence, Local [DISEASES], Humans, Prospective Studies, Medicina personalitzada, Neoplasm Recurrence, Local, Precision Medicine, Child, Therapeutics::Precision Medicine [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Cell-Free Nucleic Acids
Abstract

Abstract MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered “ready for routine use.” Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies—56% of them within early clinical trials—mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA). Significance: MAPPYACTS underlines the feasibility of molecular profiling at cancer recurrence in children on a multicenter, international level and demonstrates benefit for patients with selected key drivers. The use of cfDNA deserves validation in prospective studies. Our study highlights the need for innovative therapeutic proof-of-concept trials that address the underlying cancer complexity. This article is highlighted in the In This Issue feature, p. 1171

Published
2022

12. Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder

Author

Sébastien Küry, Frédéric Ebstein, Alice Mollé, Thomas Besnard, Ming-Kang Lee, Virginie Vignard, Tiphaine Hery, Mathilde Nizon, Grazia M.S. Mancini, Jacques C. Giltay, Benjamin Cogné, Kirsty McWalter, Wallid Deb, Hagar Mor-Shaked, Hong Li, Rhonda E. Schnur, Ingrid M. Wentzensen, Anne-Sophie Denommé-Pichon, Cynthia Fourgeux, Frans W. Verheijen, Eva Faurie, Rachel Schot, Cathy A. Stevens, Daphne J. Smits, Eileen Barr, Ruth Sheffer, Jonathan A. Bernstein, Chandler L. Stimach, Eliana Kovitch, Vandana Shashi, Kelly Schoch, Whitney Smith, Richard H. van Jaarsveld, Anna C.E. Hurst, Kirstin Smith, Evan H. Baugh, Suzanne G. Bohm, Emílie Vyhnálková, Lukáš Ryba, Capucine Delnatte, Juanita Neira, Dominique Bonneau, Annick Toutain, Jill A. Rosenfeld, Séverine Audebert-Bellanger, Brigitte Gilbert-Dussardier, Sylvie Odent, Frédéric Laumonnier, Seth I. Berger, Ann C.M. Smith, Franck Bourdeaut, Marc-Henri Stern, Richard Redon, Elke Krüger, Raphaël Margueron, Stéphane Bézieau, Jeremie Poschmann, Bertrand Isidor, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Universität Greifswald - University of Greifswald, Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University Medical Center [Utrecht], GeneDx [Gaithersburg, MD, USA], Hadassah Hebrew University Medical Center [Jerusalem], Emory University School of Medicine, Emory University [Atlanta, GA], Laboratoire de Biologie Neurovasculaire Intégrée [Angers] (CNRS UMR6214 - INSERM U771), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers, MitoVasc - 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), University of Tennessee System, Stanford University, Duke University Medical Center, University of Alabama at Birmingham [ Birmingham] (UAB), Columbia University [New York], Charles University [Prague] (CU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Baylor College of Medicine (BCM), Baylor University, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Unité neurovasculaire et troubles cognitifs (Neuvacod), Université de Poitiers, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), 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 référence Maladies Rares CLAD-Ouest [Rennes], Children's National Medical Center, National Human Genome Research Institute (NHGRI), Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Greifswald University Hospital, Research reported in this manuscript was supported by the NIH Common Fund through the Office of Strategic Coordination/Office of the NIH Director under award number U01HG007672 to V.S. Further support was obtained by funding from the German Research Foundation (SFBTR 167 A4, GRK2719 B4) to E.K, and Clinical Genetics

Subjects
Male, Heterozygote, Proteasome Endopeptidase Complex, tumor, Adolescent, T-Lymphocytes, Ubiquitin-Protein Ligases, [SDV]Life Sciences [q-bio], Mutation, Missense, UPS, ubiquitin-proteasome system, chromatin remodeling, Histones, SDG 3 - Good Health and Well-being, Loss of Function Mutation, Report, ubiquitin, Genetics, Humans, cancer, Family, BAP1, Child, deubiquitination, Germ-Line Mutation, Genetics (clinical), [SDV.GEN]Life Sciences [q-bio]/Genetics, neurodevelopment, BRCA1 Protein, Tumor Suppressor Proteins, Ubiquitination, Infant, Chromatin Assembly and Disassembly, BRCA1, Chromatin, Gene Expression Regulation, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, histone 2A, Female, Host Cell Factor C1, Ubiquitin Thiolesterase
Abstract

International audience; Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.

Published
2022

13. BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells

Author

Violette Azzoni, Julien Wicinski, Manon Macario, Martin Castagné, Pascal Finetti, Katerina Ambrosova, Célia D. Rouault, Arnaud Sergé, Anne Farina, Emilie Agavnian, Sergiu Coslet, Emmanuelle Josselin, Arnaud Guille, José Adelaide, Emmanouil Zacharioudakis, Rémy Castellano, Francois Bertucci, Daniel Birnbaum, Raphael Rodriguez, Emmanuelle Charafe-Jauffret, Christophe Ginestier, Bertucci, François, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de recherche de l'Institut Curie [Paris], Institut Curie [Paris], Université Paris sciences et lettres (PSL), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cell Nucleus, DNA Replication, Polycomb Repressive Complex 1, Cancer Research, QH573-671, [SDV]Life Sciences [q-bio], Immunology, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Biology, Cellular and Molecular Neuroscience, [SDV.CAN] Life Sciences [q-bio]/Cancer, Drug Resistance, Neoplasm, Neoplastic Stem Cells, Humans, Female, Rad51 Recombinase, Cisplatin, Homologous Recombination, Cytology, DNA Damage
Abstract

Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells’ (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance.

Published
2022

14. The role of tumor model in magnetic targeting of magnetosomes and ultramagnetic liposomes

Author

Alberto Curcio, Jose Efrain Perez, Sandra Prévéral, Alexandre Fromain, Coralie Genevois, Aude Michel, Aurore Van de Walle, Yoann Lalatonne, Damien Faivre, Christine Ménager, Claire Wilhelm, Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), TBM-Core [Bordeaux] (UMS3427 - INSERM US005), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), PHysicochimie des Electrolytes et Nanosystèmes InterfaciauX (PHENIX), Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord

Subjects
Multidisciplinary, [SDV]Life Sciences [q-bio]
Abstract

The combined passive and active targeting of tumoral tissue remains an active and relevant cancer research field. Here, we exploit the properties of two highly magnetic nanomaterials, magnetosomes and ultramagnetic liposomes, in order to magnetically target prostate adenocarcinoma tumors, implanted orthotopically or subcutaneously to take into account the role of tumor vascularization in the targeting efficiency. Analysis of organ biodistribution in vivo analysis revealed that, for all conditions, both nanomaterials accumulate mostly in the liver and spleen, with an overall low tumor retention. However, both nanomaterials were more readily identified in orthotopic tumors, reflecting their higher tumor vascularization. Additionally, a 2- and 3- fold increase in nanomaterial accumulation was achieved with magnetic targeting. In summary, ultramagnetic nanomaterials show promise mostly in the targeting of highly-vascularized orthotopic tumors.

Published
2023

15. Optogenetic control of beta-carotene bioproduction in yeast across multiple lab-scales

Author

Sylvain Pouzet, Jessica Cruz-Ramón, Matthias Le Bec, Céline Cordier, Alvaro Banderas, Simon Barral, Sara Castaño-Cerezo, Thomas Lautier, Gilles Truan, Pascal Hersen, Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANR-11-LABX-0038,CelTisPhyBio,Des cellules aux tissus: au croisement de la Physique et de la Biologie(2011), ANR-16-CE12-0025,COGEX,Contrôle automatisé de l'expression des gènes(2016), and European Project: 724813,H2020 Pilier ERC,SmartCells(2017)

Subjects
Optogenetics, Histology, beta-carotene, bioproduction, [SDV]Life Sciences [q-bio], Biomedical Engineering, Bioengineering, Saccharomyces cerevisiae, synthetic biology, yeast, metabolic engineering, Biotechnology, DIY
Abstract

Optogenetics arises as a valuable tool to precisely control genetic circuits in microbial cell factories. Light control holds the promise of optimizing bioproduction methods and maximizing yields, but its implementation at different steps of the strain development process and at different culture scales remains challenging. In this study, we aim to control beta-carotene bioproduction using optogenetics in Saccharomyces cerevisiae and investigate how its performance translates across culture scales. We built four lab-scale illumination devices, each handling different culture volumes, and each having specific illumination characteristics and cultivating conditions. We evaluated optogenetic activation and beta-carotene production across devices and optimized them both independently. Then, we combined optogenetic induction and beta-carotene production to make a light-inducible beta-carotene producer strain. This was achieved by placing the transcription of the bifunctional lycopene cyclase/phytoene synthase CrtYB under the control of the pC120 optogenetic promoter regulated by the EL222-VP16 light-activated transcription factor, while other carotenogenic enzymes (CrtI, CrtE, tHMG) were expressed constitutively. We show that illumination, culture volume and shaking impact differently optogenetic activation and beta-carotene production across devices. This enabled us to determine the best culture conditions to maximize light-induced beta-carotene production in each of the devices. Our study exemplifies the stakes of scaling up optogenetics in devices of different lab scales and sheds light on the interplays and potential conflicts between optogenetic control and metabolic pathway efficiency. As a general principle, we propose that it is important to first optimize both components of the system independently, before combining them into optogenetic producing strains to avoid extensive troubleshooting. We anticipate that our results can help designing both strains and devices that could eventually lead to larger scale systems in an effort to bring optogenetics to the industrial scale.

Published
2023

16. Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

Author

Jérémie Rosain, Anna-Lena Neehus, Jérémy Manry, Rui Yang, Jérémie Le Pen, Wassim Daher, Zhiyong Liu, Yi-Hao Chan, Natalia Tahuil, Özden Türel, Mathieu Bourgey, Masato Ogishi, Jean-Marc Doisne, Helena M. Izquierdo, Takayoshi Shirasaki, Tom Le Voyer, Antoine Guérin, Paul Bastard, Marcela Moncada-Vélez, Ji Eun Han, Taushif Khan, Franck Rapaport, Seon-Hui Hong, Andrew Cheung, Kathrin Haake, Barbara C. Mindt, Laura Pérez, Quentin Philippot, Danyel Lee, Peng Zhang, Darawan Rinchai, Fatima Al Ali, Manar Mahmoud Ahmad Ata, Mahbuba Rahman, Jessica N. Peel, Søren Heissel, Henrik Molina, Yasemin Kendir-Demirkol, Rasheed Bailey, Shuxiang Zhao, Jonathan Bohlen, Mathieu Mancini, Yoann Seeleuthner, Marie Roelens, Lazaro Lorenzo, Camille Soudée, María Elvira Josefina Paz, María Laura González, Mohamed Jeljeli, Jean Soulier, Serge Romana, Anne-Sophie L’Honneur, Marie Materna, Rubén Martínez-Barricarte, Mathieu Pochon, Carmen Oleaga-Quintas, Alexandre Michev, Mélanie Migaud, Romain Lévy, Marie-Alexandra Alyanakian, Flore Rozenberg, Carys A. Croft, Guillaume Vogt, Jean-François Emile, Laurent Kremer, Cindy S. Ma, Jörg H. Fritz, Stanley M. Lemon, András N. Spaan, Nicolas Manel, Laurent Abel, Margaret R. MacDonald, Stéphanie Boisson-Dupuis, Nico Marr, Stuart G. Tangye, James P. Di Santo, Qian Zhang, Shen-Ying Zhang, Charles M. Rice, Vivien Béziat, Nico Lachmann, David Langlais, Jean-Laurent Casanova, Philippe Gros, Jacinta Bustamante, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hannover Medical School [Hannover] (MHH), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Yong Loo Lin School of Medicine [Singapore], Hospital del Niño Jesus, San Miguel de Tucumán, Bezmiâlem Vakıf Üniversitesi, McGill University = Université McGill [Montréal, Canada], Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris], University of North Carolina System (UNC), Garvan Institute of medical research, The University of Sydney, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], East China Normal University [Shangaï] (ECNU), Sidra Medicine [Doha, Qatar], 'Juan Pedro Garrahan' National Hospital of Pediatrics, Buenos Aires, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Hopital Saint-Louis [AP-HP] (AP-HP), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Hôpital Ambroise Paré [AP-HP], Université de Montpellier (UM), Howard Hughes Medical Institute (HHMI), The Laboratory of Human Genetics of Infectious Diseases is supported in part by grants from Inserm, Paris Cité University, the St. Giles Foundation, The Rockefeller University, the Center for Clinical and Translational Science (UL1TR001866), the National Center for Research Resources and the National Center for Advancing Sciences, the National Institutes of Health (NIH), (R01AI095983, R01AI088364, R01AI163029, and U19AI162568), the National Institute of Allergy and Infectious Diseases, the French National Research Agency (ANR) under the 'Investments for the future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS Nord-Sud (ANRS-COV05), ANRS (ECTZ170784-ANRS0073), GENVIR (ANR-20-CE93-003), GENMSMD (ANR-16-CE17-0005-01), AABIFNCOV (ANR-20-CO11-0001), GenMIS-C (ANR-21-COVR-0039), SUNLIVE (ANR-19-CE15-0012-01), MAFMACRO (ANR-22-CE92-0008) grants, Ecos-NORD (ECOS N°C19S01), the Fisher Center for Alzheimer's Research Foundation, the Meyer Foundation, the JPB Foundation, the European Union’s Horizon 2020 research and innovation program (824110, EASI-Genomics), the Square Foundation, Grandir–Fonds de solidarité pour l’Enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), and REACTing-INSERM. The Laboratory of Virology and Infectious Disease was supported in part by the NIH (R01AI091707-10 to C.M.R.). J.L.P. was supported by the Francois Wallace Monahan Postdoctoral Fellowship at The Rockefeller University and the European Molecular Biology Organization Long-Term Fellowship (ALTF 380-2018). N. Marr was supported by Sidra Medicine and the Qatar National Research Fund (NPRP9-251-3-045). The Yale Center for Mendelian Genomics (UM1HG006504) was funded by the National Human Genome Research Institute, the Yale GSP Coordinating Center (U24 HG008956), and the Yale High-Performance Computing Center (S10OD018521). This research was partly supported by Calcul Québec, Compute Canada Canadian Institutes of Health Research (CIHR) Project Grant to D. Langlais. (#168959) and a CIHR Foundation Grant (to P.G.). D. Langlais was also supported by an FRQS Chercheur-Boursier Junior 1 Award and the Calgary Foundation for Innovation John R. Evans Leaders Fund. P.G. is supported by a Distinguished James McGill Professorship award from McGill University. S.M.L is supported by the NIH: R01-AI103083 and R01-AI150095. J.R. was supported by poste d’accueil Inserm'. J.R., P.B., and T.L.V were supported by the MD-PhD program of the Imagine Institute by the Bettencourt Schueller Foundation. N.L received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (852178 grant), German Research Foundation,(DFG) under Germany’s Excellence Strategy—EXC 2155—project number 390874280 and REBIRTH 'Förderung aus Mitteln des Niedersächsischen Vorab'. A.-L.N. was supported by the international PhD program of the Imagine Institute, by the Bettencourt Schueller Foundation and the fin de thèse FRM program (FDT202204015102). R.Y. was supported by the Sackler Center for Biomedicine and Nutrition, the Shapiro-Silverberg Fund for the Advancement of Translational Research at the Center for Clinical and Translational Science of the Rockefeller University, and the Research Grant Program from the Immune Deficiency Foundation. D. Lee. was supported by FRMfellowship (FDM202006011282). C.S.M was supported by an Early-Mid Career Research Fellowship from the Department of Health of the New South Wales Government of Australia. S.G.T was supported by an NHMRC Leadership 3 Investigator Grant (1176665) and NHMRC grant (1113904). M.O. was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology, the Honjo International Scholarship Foundation, and the New York Hideyo Noguchi Memorial Society. This work was supported by grants from ANRS (ECTZ118797), Sidaction (20-2-AEQ-12822-2), and FRM (EQU202103012774) to N. Manel, and H.I. was supported by fellowships from Institut Curie, Seneca Foundation (20941/PD/18), and ANRS (ECTZ171453). A.N.S. was supported in part by the European Union’s Horizon 2020 research and innovation program (789645 Marie Sklodowska-Curie grant). Y.-H.C. is supported by an A∗STAR International Fellowship. J. Bohlen is an EMBO postdoctoral fellow. We thank the NIH Tetramer Core Facility (NTCF) for providing the 5-OP-RU-loaded MR1 tetramer, which was developed jointly with Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), ANR-19-CE15-0012,SUNLIVE,Variabilité structurale et fonctionnelle des lipides complexes chez les mycobactéries : de l'assemblage de la paroi à la physiopathologie et virulence(2019), ANR-22-CE92-0008,MAFMACRO,Genetic predisposition and the role of myeloid cells in the susceptibility to mycobacterial infection(2022), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), and TÜREL, ÖZDEN

Subjects
inborn errors of immunity, Temel Bilimler, [SDV]Life Sciences [q-bio], interferon-stimulated gene, Life Sciences, Molecular Biology and Genetics, Genel Biyokimya, Genetik ve Moleküler Biyoloji, IRF1, General Biochemistry, Genetics and Molecular Biology, Mycobacterium, macrophages, interferon-γ, Yaşam Bilimleri, viruses, Cytogenetic, Natural Sciences, Moleküler Biyoloji ve Genetik, Sitogenetik
Abstract

Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/β-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/β immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/β. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/β-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/β-dependent antiviral immunity.

Published
2023

17. Force tuning through regulation of clathrin-dependent integrin endocytosis

Author

Alexander Kyumurkov, Anne-Pascale Bouin, Mathieu Boissan, Sandra Manet, Francesco Baschieri, Mathilde Proponnet-Guerault, Martial Balland, Olivier Destaing, Myriam Régent-Kloeckner, Claire Calmel, Alice Nicolas, François Waharte, Philippe Chavrier, Guillaume Montagnac, Emmanuelle Planus, Corinne Albiges-Rizo, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), Dynamique des cellules tumorales (UMR1279), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Minatec, Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE13-0022,CODECIDE,Coincidence de detection dans l'identité cellulaire(2017), Chavrier, Philippe, Coincidence de detection dans l'identité cellulaire - - CODECIDE2017 - ANR-17-CE13-0022 - AAPG2017 - VALID, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Didactique André Revuz (LDAR (URP_4434)), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Lille-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Paris Cité (UPCité)-CY Cergy Paris Université (CY), Laboratoire des technologies de la microélectronique (LTM ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), BioImaging Cell and Tissue Core Facility (PICT-IBiSA), Institut Curie [Paris], Centre de recherche de l'Institut Curie [Paris], Dynamique moléculaire de la transformation hématopoïétique (Dynamo), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
Talin, [SDV] Life Sciences [q-bio], Focal Adhesions, Integrin beta1, [SDV]Life Sciences [q-bio], Integrin beta3, Cell Biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mechanotransduction, Cellular, Clathrin, Endocytosis
Abstract

International audience; Integrin endocytosis is essential for many fundamental cellular processes. Whether and how the internalization impacts cellular mechanics remains elusive. Whereas previous studies reported the contribution of the integrin activator, talin, in force development, the involvement of inhibitors is less documented. We identified ICAP-1 as an integrin inhibitor involved in mechanotransduction by co-working with NME2 to control clathrin-mediated endocytosis of integrins at the edge of focal adhesions (FA). Loss of ICAP-1 enables β3-integrin-mediated force generation independently of β1 integrin. β3-integrin-mediated forces were associated with a decrease in β3 integrin dynamics stemming from their reduced diffusion within adhesion sites and slow turnover of FA. The decrease in β3 integrin dynamics correlated with a defect in integrin endocytosis. ICAP-1 acts as an adaptor for clathrin-dependent endocytosis of integrins. ICAP-1 controls integrin endocytosis by interacting with NME2, a key regulator of dynamin-dependent clathrin-coated pits fission. Control of clathrin-mediated integrin endocytosis by an inhibitor is an unprecedented mechanism to tune forces at FA.

Published
2023

18. High-Speed Localization Microscopy and Single-Particle Tracking (2nd edition)

Author

El Beheiry, Mohamed, Hajj, Bassam, Masson, Jean-Baptiste, Dahan, Maxime, Décision et processus Bayesiens - Decision and Bayesian Computation, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), and Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Fluorescence microscopy, Localization microscopy, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV]Life Sciences [q-bio], [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Single-molecule dynamics, Single-particle tracking
Abstract

Based on the detection of individually fluorescing molecules, localization microscopy (LM) is currently an established imaging modality in studies of cellular biology. Applied to live cells, LM provides the means to probe environments with single molecule precision and, moreover, provide information on elementary biological processes. High-speed LM involves generating discrete high-resolution snapshots of molecular distributions in living cells and single-particle tracking involves following the motion of individual molecules over time. This article details these two popular configurations of LM.

Published
2023

19. Compréhension/acceptation de la radiothérapie : un dilemme éthique résolu par une éthique de la considération et de la sollicitude

Author

de Crevoisier, Renaud, Leseur, Julie, Bouvet, C., Huguet, Florence, Lagrange, J. L., Haaser, Thibaud, Pasquier, David, Créhange, Gilles, Supiot, Stéphane, Pommier, Pascal, Roy, Amit, Berna, A., Blanchard, Pierre, Marcucci, L., Centre Eugène Marquis (CRLCC), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Université Bordeaux Montaigne (UBM), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Laboratoire d'Imagerie Translationnelle en Oncologie (LITO ), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie Centre de Protonthérapie d'Orsay, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre Léon Bérard [Lyon], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Centre Atlantique de Philosophie (CAPHI), Université de Rennes (UR)-Université de Brest (UBO)-Institut Brestois des Sciences de l'Homme et de la Société (IBSHS), Université de Brest (UBO)-Nantes Université - UFR Lettres et Langages (Nantes Univ - UFR LL), Nantes Université - pôle Humanités, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Humanités, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Université de Rennes - Faculté des sciences pharmaceutiques et biologiques (UR Pharmacie), and Université de Rennes (UR)

Subjects
Ethics, Oncology, Radiotherapy, [SDV]Life Sciences [q-bio], Beneficence, Consideration, Radiology, Nuclear Medicine and imaging, [SDV.CAN]Life Sciences [q-bio]/Cancer, Autonomy
Abstract

International audience; Purpose: Ethical questions are poorly investigated specifically in radiation oncology. The objective of the study was to identify and understand the main ethical issue in radiation oncology. Materials and methods: A quantitative analysis was based on the answers to a questionnaire of 200 professionals from 22 radiation oncology departments. The questionnaire mainly aimed to characterize the main ethical issue. A monocentric qualitative analysis was based on semi-structured interviews focused on the main identified ethical issue, carried out with eight technologists, and 20 patients undergoing radiotherapy. Results: The main ethical issue was the understanding and/or acceptance of the treatment by the patients (71 %), which frequently arises (more than once a month) (52 %), and corresponds to an ethical tension between the principles of respect for autonomy and beneficence (the good as viewed by the patient) as defined by Beauchamp and Childress. The technologists, wish the patient to be fully involved in his treatment, with the even possibility of refusing it. However, excluding paternalism and autonomic relentlessness, the technologists have the feeling of acting for the good of the patients by treating them with radiation, even if the patients are not always aware of it, because they are within a situation of vulnerability. If the hierarchy of principles is a compromise alternative, this problem is finally well resolved by the effective implementation of an ethic of consideration and solicitude, restoring the patient capabilities, i.e. the maximum development of his potentialities in his situation of vulnerability. Beyond the legal dimension, patient information is crucial and must consider the specific temporality of the patient. Conclusion: The main ethical issue in radiation oncology is the understanding and/or acceptance of the treatment involving the development of an ethic of consideration and solicitude.

Published
2023

20. MITF activity is regulated by a direct interaction with RAF proteins in melanoma cells

Author

Estrada, Charlène, Mirabal-Ortega, Liliana, Méry, Laurence, Dingli, Florent, Besse, Laetitia, Messaoudi, Cedric, Loew, Damarys, Pouponnot, Celio, Bertolotto, Corine, Eychène, Alain, Druillennec, Sabine, Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Laboratoire de Spectrométrie de Masse Protéomique, Multimodal Imaging Center (Centre d'Imagerie Multimodale) (MIC), Université Paris-Saclay, Université Paris sciences et lettres (PSL), Institut Curie [Orsay], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris sciences et lettres (PSL), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), and Pouponnot, Celio

Subjects
Cell biology, Microphthalmia-Associated Transcription Factor, integumentary system, QH301-705.5, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Article, General Biochemistry, Genetics and Molecular Biology, Gene Expression Regulation, Neoplastic, body regions, [SDV] Life Sciences [q-bio], Mice, HEK293 Cells, Cell Line, Tumor, Animals, Humans, raf Kinases, Biology (General), General Agricultural and Biological Sciences, neoplasms, Melanoma, Cell signalling
Abstract

The MITF transcription factor and the RAS/RAF/MEK/ERK pathway are two interconnected main players in melanoma. Understanding how MITF activity is regulated represents a key question since its dynamic modulation is involved in the phenotypic plasticity of melanoma cells and their resistance to therapy. By investigating the role of ARAF in NRAS-driven mouse melanoma through mass spectrometry experiments followed by a functional siRNA-based screen, we unexpectedly identified MITF as a direct ARAF partner. Interestingly, this interaction is conserved among the RAF protein kinase family since BRAF/MITF and CRAF/MITF complexes were also observed in the cytosol of NRAS-mutated mouse melanoma cells. The interaction occurs through the kinase domain of RAF proteins. Importantly, endogenous BRAF/MITF complexes were also detected in BRAF-mutated human melanoma cells. RAF/MITF complexes modulate MITF nuclear localization by inducing an accumulation of MITF in the cytoplasm, thus negatively controlling its transcriptional activity. Taken together, our study highlights a new level of regulation between two major mediators of melanoma progression, MITF and the MAPK/ERK pathway, which appears more complex than previously anticipated., The MITF transcription factor directly binds to the kinase domain of RAF kinases, including ARAF, BRAF and CRAF in melanoma cells. RAF/MITF complex promotes cytoplasmic accumulation of MITF and thus negatively regulates its transcriptional activity.

Published
2022

21. DNA methylation and hydroxymethylation characterize the identity of D1 and D2 striatal projection neurons

Author

Lucile Marion-Poll, Jean-Pierre Roussarie, Lieng Taing, Cloelia Dard-Dascot, Nicolas Servant, Yan Jaszczyszyn, Emmanuelle Jordi, Eskeatnaf Mulugeta, Denis Hervé, Déborah Bourc’his, Paul Greengard, Claude Thermes, Jean-Antoine Girault, Cell biology, Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Rockefeller University [New York], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-16-CE16-0018,EPITRACES,Traces épigénétiques neuronales des récompenses(2016)

Subjects
Neurons, Epigenomics, Interneurons, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), DNA Methylation, General Agricultural and Biological Sciences, Corpus Striatum, General Biochemistry, Genetics and Molecular Biology
Abstract

Neuronal DNA modifications differ from those in other cells, including methylation outside CpG context and abundant 5-hydroxymethylation whose relevance for neuronal identities are unclear. Striatal projection neurons expressing D1 or D2 dopamine receptors allow addressing this question, as they share many characteristics but differ in their gene expression profiles, connections, and functional roles. We compare translating mRNAs and DNA modifications in these two populations. DNA methylation differences occur predominantly in large genomic clusters including differentially expressed genes, potentially important for D1 and D2 neurons. Decreased gene body methylation is associated with higher gene expression. Hydroxymethylation differences are more scattered and affect transcription factor binding sites, which can influence gene expression. We also find a strong genome-wide hydroxymethylation asymmetry between the two DNA strands, particularly pronounced at expressed genes and retrotransposons. These results identify novel properties of neuronal DNA modifications and unveil epigenetic characteristics of striatal projection neurons heterogeneity.

Published
2022

22. Molecular Underpinnings and Environmental Drivers of Spontaneous Loss of Heterozygosity in Drosophila Intestinal Stem Cells

Author

Lara Al zouabi, Marine Stefanutti, Nick Riddiford, Natalia Rubanova, Mylène Bohec, Nicolas Servant, Allison Bardin, Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Plateforme de génomique [Institut Curie], Institut Curie [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Bardin, Allison

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract

The genome stability of adult stem cells is of particular importance as these cells maintain long-term self-renewal capacity and can contribute extensively to adult tissues. During development and aging, genome mutation leading to loss of heterozygosity (LOH) can uncover recessive phenotypes and be propagated within tissue compartments. This phenomenon occurs in normal human tissues, and is prevalent in pathological genetic conditions and cancers. While previous studies in yeast have defined distinct DNA repair mechanisms that can promote LOH, the predominant pathways underlying LOH in complex somatic tissues of multicellular organisms arenot well understood. In addition, how environmental triggers such as pathogenic bacterial infection may impact LOH is unclear. Here, we investigate the mechanisms giving rise to LOH in adult intestinal stem cells in Drosophila. Our data indicate that infection with the enteric pathogenic bacteria, Erwinia carotovora carotovora 15 but not Pseudomonas entomophila increases LOH frequency. Using whole-genome sequencing of somatic LOH events, we demonstrate that they arise primarily via mitotic recombination. Molecular features of recombination sites and genetic evidence argue against formation via break-induced replication and instead support cross-over events arising from double Holliday junction-based repair. This study provides a mechanistic understanding of mitotic recombination in stem cells in vivo, an important mediator of LOH.

Published
2022

23. BTG1 inactivation drives lymphomagenesis and promotes lymphoma dissemination through activation of BCAR1

Author

Lorric Delage, Mireille Lambert, Émilie Bardel, Cindy Kundlacz, Dimitri Chartoire, Axel Conchon, Anne-Laure Peugnet, Lucas Gorka, Patrick Auberger, Arnaud Jacquel, Carole Soussain, Olivier Destaing, Henri-Jacques Delecluse, Susanne Delecluse, Samir Merabet, Alexandra Traverse-Glehen, Gilles Salles, Emmanuel Bachy, Marc Billaud, Hervé Ghesquières, Laurent Genestier, Jean-Pierre Rouault, Pierre Sujobert, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virologie UMR1161 (VIRO), École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), C3M U1065, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Unit F100 [Heidelberg, Allemagne], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Faculty of Biosciences [Heidelberg, Allemagne], Heidelberg University, Microbiology and infectious diseases, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Institut National de la Santé et de la Recherche Médicale (INSERM), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), CNRS, UMR5242, Inst Genom Fonctionnelle Lyon,Ecole Normale Super, Weill Medical College of Cornell University [New York], Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Génétique moléculaire, signalisation et cancer (GMSC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS)

Subjects
[SDV]Life Sciences [q-bio], Immunology, Cell Biology, Hematology, Biochemistry
Abstract

Understanding the functional role of mutated genes in cancer is required to translate the findings of cancer genomics into therapeutic improvement. BTG1 is recurrently mutated in the MCD/C5 subtype of diffuse large B-cell lymphoma (DLBCL), which is associated with extranodal dissemination. Here, we provide evidence that Btg1 knock out accelerates the development of a lethal lymphoproliferative disease driven by Bcl2 overexpression. Furthermore, we show that the scaffolding protein BCAR1 is a BTG1 partner. Moreover, after BTG1 deletion or expression of BTG1 mutations observed in patients with DLBCL, the overactivation of the BCAR1-RAC1 pathway confers increased migration ability in vitro and in vivo. These modifications are targetable with the SRC inhibitor dasatinib, which opens novel therapeutic opportunities in BTG1 mutated DLBCL.

Published
2022

24. Introduction to the special issue on 'unconventional T cells'

Author

Legoux, François, Lantz, Olivier, Institut de Génétique et Développement de Rennes (IGDR), 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 ), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], ANR-10-IDEX-0001-02 PSL, Agence Nationale de la Recherche, ERC-2019-AdG-885435, European Research Council, ANR-16-CE15-0020,MAIT,Biologie des cellules MAIT in vivo en situation normale ou pathologique(2016), and ANR-20-CE15-0028,MAIT-repair,Mécanisme de la fonction de réparation tissulaire des lymphocytes MAIT(2020)

Subjects
T-Lymphocytes, [SDV]Life Sciences [q-bio], Immunology, Humans, Immunology and Allergy
Abstract

International audience

Published
2022

25. Cell clusters adopt a collective amoeboid mode of migration in confined nonadhesive environments

Author

Diane-Laure Pagès, Emmanuel Dornier, Jean de Seze, Emilie Gontran, Ananyo Maitra, Aurore Maciejewski, Li Wang, Rui Luan, Jérôme Cartry, Charlotte Canet-Jourdan, Joël Raingeaud, Grégoire Lemahieu, Marceline Lebel, Michel Ducreux, Maximiliano Gelli, Jean-Yves Scoazec, Mathieu Coppey, Raphaël Voituriez, Matthieu Piel, Fanny Jaulin, Dynamique des cellules tumorales (UMR1279), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université Paris-Saclay, Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Jean Perrin (LJP), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-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), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pierre-Gilles de Gennes pour la Microfluidique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Département de chirurgie viscérale [Gustave Roussy], Département de biologie et pathologie médicales [Gustave Roussy], Laboratoire de Physique Théorique de la Matière Condensée (LPTMC), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and raingeaud, joel

Subjects
[SDV] Life Sciences [q-bio], Multidisciplinary, [SDV]Life Sciences [q-bio]
Abstract

International audience; Cell migration is essential to living organisms and deregulated in cancer. Single cell’s migration ranges from traction-dependent mesenchymal motility to contractility-driven propulsive amoeboid locomotion, but collective cell migration has only been described as a focal adhesion–dependent and traction-dependent process. Here, we show that cancer cell clusters, from patients and cell lines, migrate without focal adhesions when confined into nonadhesive microfabricated channels. Clusters coordinate and behave like giant super cells, mobilizing their actomyosin contractility at the rear to power their migration. This polarized cortex does not sustain persistent retrograde flows, of cells or actin, like in the other modes of migration but rather harnesses fluctuating cell deformations, or jiggling. Theoretical physical modeling shows this is sufficient to create a gradient of friction forces and trigger directed cluster motion. This collective amoeboid mode of migration could foster metastatic spread by enabling cells to cross a wide spectrum of environments.

Published
2022

26. Migration collective cellulaire sur des substrats courbes cylindriques

Author

Glentis, Alexandros, Blanch-Mercader, Carles, Balasubramaniam, Lakshmi, Saw, Thuan Beng, d’Alessandro, Joseph, Janel, Sebastien, Douanier, Audrey, Delaval, Benedicte, Lafont, Frank, Lim, Chwee Teck, Delacour, Delphine, Prost, Jacques, Xi, Wang, Ladoux, Benoit, Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Mechanobiology Institute [Singapore] (MBI), National University of Singapore (NUS), CHU Lille, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Laboratoire Physico-Chimie Curie [Institut Curie] [PCC], Mechanobiology Institute [Singapore] [MBI], Institut Jacques Monod [IJM (UMR_7592)], Centre de recherche en Biologie cellulaire de Montpellier [CRBM], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL], Cellular Microbiology and Physics of Infection Group [Lille] (CMPI), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, This work was supported by the LABEX 'Who Am I?' (ANR-11-LABX-0071) (to B.L.), the European Research Council (ERC) (grant no. Adv-101019835) (to B.L.), the Marie Skłodowska-Curie Actions, Individual Fellowship, project 846449 (to W.X.), People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) under REA grant agreement no. PCOFUND-GA-2013-609102, through the PRESTIGE program coordinated by Campus France (to W.X.), funding from the Labex Who Am I? (ANR-11-LABX-0071) and the 'Initiatives d’excellence' (Idex ANR-11-IDEX-0005-02) transverse project BioMechanOE (TP5) (to W.X.), the Agence Nationale de la Recherche (ANR) 'POLCAM' ANR-17-CE13-0013 funded Glentis et al., Sci. Adv. 8, eabn5406 (2022) 14 September 2022 by the French government (to B.L.), the SystemsX EpiPhysX consortium funding (to C.B.-M.), the NR PRC LUCELL grant (ANR-19-CE13-0014-01) (to B.D.), the ANR-10-EQPX-04-01 (to F.L.), the European Regional Development Fund (FEDER-12001407) (to F.L.), the Groupama Foundation—Research Prize for Rare Diseases 2017 (to D.D. and W.X.), the ANR 'LUCELL' ANR-19-CE13-0014 funded by the French government (to B.D. and D.D.), the Fondation pour la Recherche Médicale (FRM) (to D.D.), the Université de Paris IDEX, ANR-18-IDEX-0001, funded by the French government through its 'Investments for the Future' program (to D.D.), the Human Frontier Science Program, RGP0038/2018 (to D.D., C.T.L., T.B.S., J.P., and W.X.), Lee Kuan Yew Postdoctoral fellowship and Tier 1 grant (R-397-000-320-114) from the Ministry of Education (MOE), Singapore (to T.B.S.), and the National Research Foundation, Singapore, under the Mechanobiology Institute at the National University of Singapore (to C.T.L.)., ANR-11-LABX-0071,WHO AM I,Determinants de l'Identité : de la molécule à l'individu(2011), Delacour, Delphine, and Determinants de l'Identité : de la molécule à l'individu - - WHO AM I2011 - ANR-11-LABX-0071 - LABX - VALID

Subjects
[SDV] Life Sciences [q-bio], [PHYS]Physics [physics], Multidisciplinary, [SDV]Life Sciences [q-bio]
Abstract

View the article online https://www.science.org/doi/10.1126/sciadv.abn5406; International audience; Three-dimensional collective epithelial rotation around a given axis represents a coordinated cellular movement driving tissue morphogenesis and transformation. Questions regarding these behaviors and their relationship with substrate curvatures are intimately linked to spontaneous active matter processes and to vital morphogenetic and embryonic processes. Here, using interdisciplinary approaches, we study the dynamics of epithelial layers lining different cylindrical surfaces. We observe large-scale, persistent, and circumferential rotation in both concavely and convexly curved cylindrical tissues. While epithelia of inverse curvature show an orthogonal switch in actomyosin network orientation and opposite apicobasal polarities, their rotational movements emerge and vary similarly within a common curvature window. We further reveal that this persisting rotation requires stable cell-cell adhesion and Rac-1-dependent cell polarity. Using an active polar gel model, we unveil the different relationships of collective cell polarity and actin alignment with curvatures, which lead to coordinated rotational behavior despite the inverted curvature and cytoskeleton order.

Published
2022

27. Human Cytomegalovirus Modifies Placental Small Extracellular Vesicle Composition to Enhance Infection of Fetal Neural Cells In Vitro

Author

Mathilde Bergamelli, Hélène Martin, Yann Aubert, Jean-Michel Mansuy, Marlène Marcellin, Odile Burlet-Schiltz, Ilse Hurbain, Graça Raposo, Jacques Izopet, Thierry Fournier, Alexandra Benchoua, Mélinda Bénard, Marion Groussolles, Géraldine Cartron, Yann Tanguy Le Gac, Nathalie Moinard, Gisela D’Angelo, Cécile E. Malnou, Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), 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), Pathologies et épithéliums : prévention, innovation, traitements, évaluation (UR 4267) (PEPITE), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Virologie [Toulouse], CHU Toulouse [Toulouse], Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et Pharmacotoxicologie Placentaire Humaine (U1139), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Centre d'Epidémiologie et de Recherche en santé des POPulations (CERPOP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Développement Embryonnaire, Fertilité et Environnement (DEFE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Virologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Physiopathologie et pharmacotoxicologie placentaire humaine : Microbiote pré & post natal (3PHM - UMR-S 1139), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), and ANR-11-LABX-0038,CelTisPhyBio,Des cellules aux tissus: au croisement de la Physique et de la Biologie(2011)

Subjects
Proteomics, placenta, [SDV]Life Sciences [q-bio], Cytomegalovirus, cytotrophoblast, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, hCMV, congenital infection, Infectious Diseases, extracellular vesicles, Pregnancy, Virology, Cytomegalovirus Infections, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Humans, Female
Abstract

International audience; Although placental small extracellular vesicles (sEVs) are extensively studied in the context of pregnancy, little is known about their role during viral congenital infection, especially at the beginning of pregnancy. In this study, we examined the consequences of human cytomegalovirus (hCMV) infection on sEVs production, composition, and function using an immortalized human cytotrophoblast cell line derived from first trimester placenta. By combining complementary approaches of biochemistry, electron microscopy, and quantitative proteomic analysis, we showed that hCMV infection increases the yield of sEVs produced by cytotrophoblasts and modifies their protein content towards a potential proviral phenotype. We further demonstrate that sEVs secreted by hCMV-infected cytotrophoblasts potentiate infection in naive recipient cells of fetal origin, including human neural stem cells. Importantly, these functional consequences are also observed with sEVs prepared from an ex vivo model of infected histocultures from early placenta. Based on these findings, we propose that placental sEVs could be important actors favoring viral dissemination to the fetal brain during hCMV congenital infection.

Published
2022

28. Challenges of intracellular visualization using virtual and augmented reality

Author

Cesar Augusto Valades-Cruz, Ludovic Leconte, Gwendal Fouche, Thomas Blanc, Nathan Van Hille, Kevin Fournier, Tao Laurent, Benjamin Gallean, Francois Deslandes, Bassam Hajj, Emmanuel Faure, Ferran Argelaguet, Alain Trubuil, Tobias Isenberg, Jean-Baptiste Masson, Jean Salamero, Charles Kervrann, Space-timE RePresentation, Imaging and cellular dynamics of molecular COmplexes (SERPICO), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 3D interaction with virtual environments using body and mind (Hybrid), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-RÉALITÉ VIRTUELLE, HUMAINS VIRTUELS, INTERACTIONS ET ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Interdisciplinaire des Sciences du Numérique (LISN), Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Image & Interaction (ICAR), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Analysis and Visualization (AVIZ), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Interdisciplinaire des Sciences du Numérique (LISN), Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Interaction avec l'Humain (IaH), Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Décision et processus Bayesiens - Decision and Bayesian Computation, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-11-LABX-0038,CelTisPhyBio,Des cellules aux tissus: au croisement de la Physique et de la Biologie(2011), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), and ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019)

Subjects
[SDV]Life Sciences [q-bio], virtual reality, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, bioimaging, intracellular imaging, multi-dimensional biological data, augmented reality, [INFO.INFO-GR]Computer Science [cs]/Graphics [cs.GR]
Abstract

International audience; Microscopy image observation is commonly performed on 2D screens, which limits human capacities to grasp volumetric, complex, and discrete biological dynamics. With the massive production of multidimensional images (3D + time, multi-channels) and derived images (e.g., restored images, segmentation maps, and object tracks), scientists need appropriate visualization and navigation methods to better apprehend the amount of information in their content. New modes of visualization have emerged, including virtual reality (VR)/ augmented reality (AR) approaches which should allow more accurate analysis and exploration of large time series of volumetric images, such as those produced by the latest 3D + time fluorescence microscopy. They include integrated algorithms that allow researchers to interactively explore complex spatiotemporal objects at the scale of single cells or multicellular systems, almost in a real time manner. In practice, however, immersion of the user within 3D + time microscopy data represents both a paradigm shift in human-image interaction and an acculturation challenge, for the concerned community. To promote a broader adoption of these approaches by biologists, further dialogue is needed between the bioimaging community and the VR&AR developers.

Published
2022

29. BRN2 is a non-canonical melanoma tumor-suppressor

Author

Pierre Sohier, Luis Sánchez-del-Campo, Nisamanee Charoenchon, Colin Kenny, Madeleine Le Coz, Colin R. Goding, Lionel Larue, Véronique Delmas, Valérie Petit, Alain Sarasin, Eiríkur Steingrímsson, Zackie Aktary, Jérémy H. Raymond, Dies Meijer, Franck Gesbert, Michael Hamm, Irwin Davidson, Robert A. Cornell, Laura Mosteo, Florian Rambow, Alfonso Bellacosa, Göran Jönsson, Marie Pouteaux, Martin Lauss, Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Carver College of Medicine [Iowa City], University of Iowa [Iowa City], Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Mahidol University [Bangkok], Fox Chase Cancer Center, University of Oxford [Oxford], Lund University [Lund], University of Edinburgh, University of Iceland [Reykjavik], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Carver College of Medicine, University of Iowa, University of Oxford, and delmas, veronique

Subjects
0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Skin Neoplasms, Carcinogenesis, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Haploinsufficiency, Cohort Studies, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, CDKN2A, Genes, Tumor Suppressor, RNA, Small Interfering, Melanoma, Multidisciplinary, biology, Microphthalmia-associated transcription factor, Immunohistochemistry, Gene Expression Regulation, Neoplastic, Mechanisms of disease, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Disease Progression, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Proto-Oncogene Proteins B-raf, Chromatin Immunoprecipitation, DNA Copy Number Variations, Science, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Context (language use), Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Animals, Humans, PTEN, Transcription factor, neoplasms, Cell Proliferation, Homeodomain Proteins, Microphthalmia-Associated Transcription Factor, POU domain, PTEN Phosphohydrolase, General Chemistry, Microarray Analysis, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Mutation, POU Domain Factors, biology.protein, Cancer research, Gene expression
Abstract

While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600E PtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression., The transcription factor BRN2 regulates melanoma migration and invasion, but its role during melanoma initiation is unclear. Here the authors show that BRN2 is a haplo-insufficient tumour suppressor that positively regulates PTEN expression and in the context of BRAF mutation and heterozygous PTEN, BRN2 loss promotes melanoma initiation and progression.

Published
2021

30. Le mot des coordinatrices

Author

Graca Raposo, Chantal M. Boulanger, Clotilde Théry, Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Immunité et cancer (U932), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]

Subjects
0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, [SDV]Life Sciences [q-bio], 030220 oncology & carcinogenesis, General Medicine, ComputingMilieux_MISCELLANEOUS, General Biochemistry, Genetics and Molecular Biology, 030304 developmental biology
Abstract

International audience; No abstract available

Published
2021

31. Surface tension of model tissues during malignant transformation and epithelial–mesenchymal transition

Author

Irène Nagle, Alain Richert, Michael Quinteros, Sébastien Janel, Edgar Buysschaert, Nathalie Luciani, Henry Debost, Véronique Thevenet, Claire Wilhelm, Céline Prunier, Frank Lafont, Teresita Padilla-Benavides, Mathieu Boissan, Myriam Reffay, Matière et Systèmes Complexes (MSC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Wesleyan University, Cellular Microbiology and Physics of Infection Group [Lille] (CMPI), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 (PLBS), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This work was supported by the Research Program Emergence(s) de la ville de Paris (Grant MAGIC Project), the French Defense Procurement Agency (DGA-AID), France, and Wesleyan University institutional funds., ANR-11-LABX-0071,WHO AM I,Determinants de l'Identité : de la molécule à l'individu(2011), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
[PHYS]Physics [physics], [SDV]Life Sciences [q-bio], Cell Biology, Developmental Biology
Abstract

International audience; Epithelial–mesenchymal transition is associated with migration, invasion, and metastasis. The translation at the tissue scale of these changes has not yet been enlightened while being essential in the understanding of tumor progression. Thus, biophysical tools dedicated to measurements on model tumor systems are needed to reveal the impact of epithelial–mesenchymal transition at the collective cell scale. Herein, using an original biophysical approach based on magnetic nanoparticle insertion inside cells, we formed and flattened multicellular aggregates to explore the consequences of the loss of the metastasis suppressor NME1 on the mechanical properties at the tissue scale. Multicellular spheroids behave as viscoelastic fluids, and their equilibrium shape is driven by surface tension as measured by their deformation upon magnetic field application. In a model of breast tumor cells genetically modified for NME1, we correlated tumor invasion, migration, and adhesion modifications with shape maintenance properties by measuring surface tension and exploring both invasive and migratory potential as well as adhesion characteristics.

Published
2022

32. Rational control of off‐state heterogeneity in a photoswitchable fluorescent protein provides switching contrast enhancement

Author

Angela Mantovanelli, A. Gorel, Dominique Bourgeois, M. Hilpert, Gabriela Nass Kovacs, Mark S. Hunter, Sébastien Boutet, Ninon Zala, Kiyoshi Ueda, Jason E. Koglin, Andrew Aquila, Michel Sliwa, Ilme Schlichting, M. Stricker, Stefan Jakobs, Kensuke Tono, Martin Weik, Virgile Adam, Anne-Sophie Banneville, Lucas Martinez Uriarte, T. Domratcheva, Michel Thépaut, Mengning Liang, Oleksandr Glushonkov, Martin Byrdin, Giorgio Schirò, Marie Luise Grünbein, Robert L. Shoeman, Kyprianos Hadjidemetriou, Thomas R. M. Barends, Sergio Carbajo, Nina Eleni Christou, Thomas J. Lane, Victor Bezchastnov, Daehyun You, Tadeo Moreno Chicano, Lutz Foucar, Marco Cammarata, Nickels A. Jensen, C.M. Roome, Jacques-Philippe Colletier, Marco Kloos, Franck Fieschi, Eugenio de la Mora, Mariam El Khatib, Nicolas Coquelle, Shigeki Owada, Matthew Seaberg, R. Bruce Doak, Karol Nass, Joyce Woodhouse, Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Department of NanoBiophotonics [Göttingen], Max Planck Institute for Biophysical Chemistry (MPI-BPC), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Max Planck Institute for Medical Research [Heidelberg], Max-Planck-Gesellschaft, Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory (SLAC), Stanford University-Stanford University, Max-Planck-Institut für Medizinische Forschung, Institut de Physique de Rennes (IPR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), RIKEN SPring-8 Center [Hyogo] (RIKEN RSC), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Japan Synchrotron Radiation Research Institute [Hyogo] (JASRI), Tohoku University [Sendai], Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l'Environnement - UMR 8516 (LASIRE), Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry, Lomonosov Moscow State University, Lomonosov Moscow State University (MSU), The XFEL experiments were carried out at BL2-EH3 of SACLA with the approval of the Japan Synchrotron Radiation Research Institute (JASRI, Proposal No. 2018 A8026, 27–29 July 2018) and at the CXI beamline at the LCLS (Proposal No. LM47 (23–27 June 2016) and LR38 (22–26 February 2018). We warmly thank the SACLA and LCLS staff for assistance. Use of the LCLS, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract no. DE-AC02-76SF00515. Part of the sample injector used at LCLS for this research was funded by the National Institutes of Health, P41 GM103393, formerly P41RR001209. We acknowledge support from the Max Planck Society. The study was supported by travel grants from the CNRS (GoToXFEL) to MW, an ANR grant to MW, MC, MSl (BioXFEL), a PhD fellowship from Lille University to LMU and an MENESR – Univ. Grenoble Alpes fellowship to KH. This work was partially carried out at the platforms of the Grenoble Instruct-ERIC center (IBS and ISBG, UMS 3518 CNRS-CEA-UGA-EMBL) within the Grenoble Partnership for Structural Biology (PSB)., ANR-17-CE11-0047,Cryo-PALM,Microscopie super-résolution par localisation de molécules uniques à température cryogénique.(2017), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Publica

Subjects
serial femtosecond crystallography, [SDV]Life Sciences [q-bio], RESOLFT, Green Fluorescent Proteins, nanoscopy, Atomic, quantum chemistry, Particle and Plasma Physics, Theoretical and Computational Chemistry, Microscopy, Side chain, switching contrast, Escherichia coli, Nuclear, Physical and Theoretical Chemistry, [PHYS]Physics [physics], Chemical Physics, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, photoswitchable fluorescent proteins, Resolution (electron density), Molecular, Chromophore, Fluorescence, Atomic and Molecular Physics, and Optics, Luminescent Proteins, Femtosecond, Biophysics, Generic health relevance, Biological imaging, Physical Chemistry (incl. Structural)
Abstract

Reversibly photoswitchable fluorescent proteins are essential markers for advanced biological imaging, and optimization of their photophysical properties underlies improved performance and novel applications. Here we establish a link between photoswitching contrast, a key parameter that largely dictates the achievable resolution in nanoscopy applications, and chromophore conformation in the non-fluorescent state of rsEGFP2, a widely employed label in REversible Saturable OpticaL Fluorescence Transitions (RESOLFT) microscopy. Upon illumination, the cis chromophore of rsEGFP2 isomerizes to two distinct off-state conformations, trans1 and trans2, located on either side of the V151 side chain. Reducing or enlarging the side chain at this position (V151A and V151L variants) leads to single off-state conformations that exhibit higher and lower switching contrast, respectively, compared to the rsEGFP2 parent. The combination of structural information obtained by serial femtosecond crystallography with high-level quantum chemical calculations and with spectroscopic and photophysical data determined in vitro suggests that the changes in switching contrast arise from blue- and red-shifts of the absorption bands associated to trans1 and trans2, respectively. Thus, due to elimination of trans2, the V151A variants of rsEGFP2 and its superfolding variant rsFolder2 display a more than two-fold higher switching contrast than their respective parent proteins, both in vitro and in E. coli cells. The application of the rsFolder2-V151A variant is demonstrated in RESOLFT nanoscopy. Our study rationalizes the connection between structural and photophysical chromophore properties and suggests a means to rationally improve fluorescent proteins for nanoscopy applications.

Published
2022

33. Tyro3 Targeting as a Radiosensitizing Strategy in Bladder Cancer through Cell Cycle Dysregulation

Author

Linda Silina, Florent Dufour, Audrey Rapinat, Cécile Reyes, David Gentien, Fatlinda Maksut, François Radvanyi, Pierre Verrelle, Isabelle Bernard-Pierrot, Frédérique Mégnin-Chanet, Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Chimie et modélisation pour la biologie du cancer (CMBC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre de recherche de l'Institut Curie [Paris], Institut Curie [Paris], Université Clermont Auvergne (UCA), and Bernard-Pierrot, Isabelle

Subjects
bladder cancer, TYRO3, radiosensitivity, TAM receptors, receptor tyrosine kinase, NanoString, [SDV]Life Sciences [q-bio], Cell Cycle, Organic Chemistry, Receptor Protein-Tyrosine Kinases, General Medicine, Cystectomy, Catalysis, Computer Science Applications, Inorganic Chemistry, [SDV] Life Sciences [q-bio], Urinary Bladder Neoplasms, Quality of Life, Humans, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract

International audience; Bladder cancer is a common cancer; it is the tenth most common cancer in the world. Around one fourth of all diagnosed patients have muscle-invasive bladder cancer (MIBC), characterized by advanced tumors and which remains a lethal disease. The standard treatment for MIBC is the bladder removal by surgery. However, bladder-preserving alternatives are emerging by combining chemotherapy, radiotherapy and minimal surgery, aiming to increase the patient’s quality of life. The aim of the study was to improve these treatments by investigating a novel approach where in addition to radiotherapy, a receptor, TYRO3, a member of TAM receptor tyrosine kinase family known to be highly expressed on the bladder cancer cells and involved in the control of cell survival is targeted. For this, we evaluated the influence of TYRO3 expression levels on a colony or cell survival assays, DNA damage, γH2AX foci formation, gene expression profiling and cell cycle regulation, after radiation on different bladder cell models. We found that TYRO3 expression impacts the radiation response via the cell cycle dysregulation with noeffets on the DNA repair. Therefore, targeting TYRO3 is a promising sensitization marker that could be clinically employed in future treatments.

Published
2022

34. RAB6 and dynein drive post-Golgi apical transport to prevent neuronal progenitor delamination

Author

Jean‐Baptiste Brault, Sabine Bardin, Marusa Lampic, Jacopo A Carpentieri, Laure Coquand, Maxime Penisson, Hugo Lachuer, Guiliana Soraya Victoria, Sarah Baloul, Fatima El Marjou, Gaelle Boncompain, Stephanie Miserey‐Lenkei, Richard Belvindrah, Vincent Fraisier, Fiona Francis, Franck Perez, Bruno Goud, Alexandre D Baffet, Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Francis, Fiona, Institut Curie [Paris], BioImaging Cell and Tissue Core Facility (PICT-IBiSA), and Goud, Bruno

Subjects
Neurons, dynein, polarized trafficking, [SDV]Life Sciences [q-bio], Dyneins, Golgi Apparatus, Biochemistry, Microtubules, neocortex development, [SDV] Life Sciences [q-bio], cell polarity, RAB6, rab GTP-Binding Proteins, Genetics, Humans, Molecular Biology, Microtubule-Associated Proteins
Abstract

International audience; Radial glial (RG) cells are the neural stem cells of the developing neocortex. Apical RG (aRG) cells can delaminate to generate basal RG (bRG) cells, a cell type associated with human brain expansion. Here, we report that aRG delamination is regulated by the post-Golgi secretory pathway. Using in situ subcellular live imaging, we show that post-Golgi transport of RAB6+ vesicles occurs toward the minus ends of microtubules and depends on dynein. We demonstrate that the apical determinant Crumbs3 (CRB3) is also transported by dynein. Double knockout of RAB6A/A' and RAB6B impairs apical localization of CRB3 and induces a retraction of aRG cell apical process, leading to delamination and ectopic division. These defects are phenocopied by knockout of the dynein activator LIS1. Overall, our results identify a RAB6-dynein-LIS1 complex for Golgi to apical surface transport in aRG cells, and highlights the role of this pathway in the maintenance of neuroepithelial integrity.

Published
2022

35. Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients Age 60 Years and Younger: Long-Term Results of the Randomized Phase II PRECIS Study

Author

Houillier, Caroline, Dureau, S, Taillandier, Luc, Houot, Roch, Chinot, O., Molucon-Chabrot, Cécile, Schmitt, Anna, Gressin, Rémy, Choquet, Sylvain, Damaj, Gandhi, Peyrade, Frédéric, Abraham, Julie, Delwail, V, Gyan, Emmanuel, Sanhes, Laurence, Cornillon, Jerome, Garidi, Reda, Delmer, Alain, Al Jijakli, Ahmad, Morel, Pierre, Waultier, Agathe, Paillassa, Jérôme, Chauchet, A, Gastinne, Thomas, Laadhari, Mouna, Plissonnier, Anne-Sophie, Feuvret, Loïc, Cassoux, Nathalie, Touitou, Valerie, Ricard, Jean-Damien, Hoang-Xuan, Khe, Soussain, Carole, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris], Centre Hospitalier Universitaire de Nancy (CHU Nancy), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Louise Michel [Clermont-Ferrand], CHU Clermont-Ferrand, Institut Bergonié [Bordeaux], UNICANCER, Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Amiens-Picardie, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU Limoges, CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Investigation Clinique [Tours] CIC 1415 (CIC ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Saint Jean de Perpignan, Institut de Cancérologie Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier de Lens, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Immunité et cancer (U932), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Cancer Research, Adolescent, Lymphoma, [SDV]Life Sciences [q-bio], Hematopoietic Stem Cell Transplantation, Middle Aged, Transplantation, Autologous, Combined Modality Therapy, Central Nervous System Neoplasms, Young Adult, Oncology, Antineoplastic Combined Chemotherapy Protocols, Humans, Neoplasm Recurrence, Local
Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We previously reported the results of a randomized phase II study in patients with newly diagnosed primary CNS lymphoma (age 18-60 years). Patients were treated with high-dose methotrexate-based induction chemotherapy followed by whole-brain radiotherapy (WBRT) or high-dose chemotherapy (thiotepa-busulfan-cyclophosphamide) with autologous stem-cell transplantation (ASCT). The median follow-up was 33 months. In this report, we provide long-term data (median follow-up, 8 years) regarding the outcomes and toxicities. Fifty-three and 44 patients received induction chemotherapy followed by WBRT or ASCT, respectively. Their 8-year event-free survival from random assignment was 67% and 39% in the ASCT and WBRT arms, respectively ( P = .03), with a significantly lower risk of relapse after ASCT (hazard ratio, 0.13; P < .001). One third of patients who relapsed after WBRT were alive after salvage treatment. Five and four patients died of ASCT and WBRT-related toxicities, respectively. The 8-year overall survival was 69% and 65% in the ASCT and WBRT arms, respectively (not significant). Balance (52% v 10%, P ≤ 0.001) and neurocognition (64% v 13%, P < .001) significantly deteriorated after WBRT compared with ASCT during the follow-up. This study shows that 40 Gy WBRT should be avoided in first-line treatment because of its neurotoxicity and suboptimal efficacy in reducing relapses while ASCT appears to be highly efficient in preventing relapses.

Published
2022

36. CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas

Author

Leticia Laura Niborski, Paul Gueguen, Mengliang Ye, Allan Thiolat, Rodrigo Nalio Ramos, Pamela Caudana, Jordan Denizeau, Ludovic Colombeau, Raphaël Rodriguez, Christel Goudot, Jean-Michel Luccarini, Anne Soudé, Bruno Bournique, Pierre Broqua, Luigia Pace, Sylvain Baulande, Christine Sedlik, Jean-Pierre Quivy, Geneviève Almouzni, José L. Cohen, Elina Zueva, Joshua J. Waterfall, Sebastian Amigorena, Eliane Piaggio, Institut Curie [Paris], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Inventiva [Daix], Dynamique du noyau [Institut Curie], Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ALMOUZNI, Geneviève, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique et biologie des cancers (U830), and AMIGORENA, Sebastian

Subjects
Multidisciplinary, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, General Physics and Astronomy, General Chemistry, Methyltransferases, CD8-Positive T-Lymphocytes, Lymphocyte Activation, General Biochemistry, Genetics and Molecular Biology, Epigenesis, Genetic, Repressor Proteins, [SDV] Life Sciences [q-bio], Lymphocytes, Tumor-Infiltrating, Humans, Melanoma
Abstract

Tumor-infiltrating CD8 + T cells progressively lose functionality and fail to reject tumors. The underlying mechanism and re-programing induced by checkpoint blockers are incompletely understood. We show here that genetic ablation or pharmacological inhibition of histone lysine methyltransferase Suv39h1 delays tumor growth and potentiates tumor rejection by anti-PD-1. In the absence of Suv39h1, anti-PD-1 induces alternative activation pathways allowing survival and differentiation of IFNγ and Granzyme B producing effector cells that express negative checkpoint molecules, but do not reach final exhaustion. Their transcriptional program correlates with that of melanoma patients responding to immune-checkpoint blockade and identifies the emergence of cytolytic-effector tumor-infiltrating lymphocytes as a biomarker of clinical response. Anti-PD-1 favors chromatin opening in loci linked to T-cell activation, memory and pluripotency, but in the absence of Suv39h1, cells acquire accessibility in cytolytic effector loci. Overall, Suv39h1 inhibition enhances anti-tumor immune responses, alone or combined with anti-PD-1, suggesting that Suv39h1 is an “epigenetic checkpoint” for tumor immunity.

Published
2022

37. CENP-A Regulation and Cancer

Author

Charlène Renaud-Pageot, Jean-Pierre Quivy, Marina Lochhead, Geneviève Almouzni, Université Paris sciences et lettres (PSL), Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Dynamique du noyau [Institut Curie], and Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], Cell Biology, macromolecular substances, Developmental Biology
Abstract

International audience; In mammals, CENP-A, a histone H3 variant found in the centromeric chromatin, is critical for faithful chromosome segregation and genome integrity maintenance through cell divisions. Specifically, it has dual functions, enabling to define epigenetically the centromere position and providing the foundation for building up the kinetochore. Regulation of its dynamics of synthesis and deposition ensures to propagate proper centromeres on each chromosome across mitosis and meiosis. However, CENP-A overexpression is a feature identified in many cancers. Importantly, high levels of CENP-A lead to its mislocalization outside the centromere. Recent studies in mammals have begun to uncover how CENP-A overexpression can affect genome integrity, reprogram cell fate and impact 3D nuclear organization in cancer. Here, we summarize the mechanisms that orchestrate CENP-A regulation. Then we review how, beyond its centromeric function, CENP-A overexpression is linked to cancer state in mammalian cells, with a focus on the perturbations that ensue at the level of chromatin organization. Finally, we review the clinical interest for CENP-A in cancer treatment.

Published
2022

38. Single-cell RNA-seq-based proteogenomics identifies glioblastoma-specific transposable elements encoding HLA-I-presented peptides

Author

Pierre-Emmanuel Bonté, Yago A. Arribas, Antonela Merlotti, Montserrat Carrascal, Jiasi Vicky Zhang, Elina Zueva, Zev A. Binder, Cécile Alanio, Christel Goudot, Sebastian Amigorena, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Instituto de Investigaciones Biomedicas de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Perelman School of Medicine, University of Pennsylvania, Institut Curie [Paris], AMIGORENA, Sebastian, Institut National de la Santé et de la Recherche Médicale (France), Centre National de la Recherche Scientifique (France), and Ligue Nationale contre le Cancer (France)

Subjects
non-coding genome, cancer immunotherapy, single-cell RNA-seq, [SDV]Life Sciences [q-bio], Histocompatibility Antigens Class I, glioblastoma, immunopeptidomics, General Biochemistry, Genetics and Molecular Biology, neoantigen, [SDV] Life Sciences [q-bio], endogenous retrovirus, non-canonical proteome, DNA Transposable Elements, Humans, HLA-I, RNA-Seq, transposable elements, Peptides, Proteogenomics
Abstract

We analyze transposable elements (TEs) in glioblastoma (GBM) patients using a proteogenomic pipeline that combines single-cell transcriptomics, bulk RNA sequencing (RNA-seq) samples from tumors and healthy-tissue cohorts, and immunopeptidomic samples. We thus identify 370 human leukocyte antigen (HLA)-I-bound peptides encoded by TEs differentially expressed in GBM. Some of the peptides are encoded by repeat sequences from intact open reading frames (ORFs) present in up to several hundred TEs from recent long interspersed nuclear element (LINE)-1, long terminal repeat (LTR), and SVA subfamilies. Other HLA-I-bound peptides are encoded by single copies of TEs from old subfamilies that are expressed recurrently in GBM tumors and not expressed, or very infrequently and at low levels, in healthy tissues (including brain). These peptide-coding, GBM-specific, highly recurrent TEs represent potential tumor-specific targets for cancer immunotherapies., We thank all the U932 members, Olivier Lantz, Maude Delost, Nathalie Amzallag, and Florence Faure, for helpful discussions. Also, we are grateful to Joshua J. Waterfall for helpful discussion and bioinformatics advice. In addition, we thank the core facilities at Curie Institute, including the Bioinformatics groups. S.A. received funding from the Institut Curie, Institut National de la Sante´ et de la Recherche Me´ dicale, and Centre National de la Recherche Scientifique. This work has received support under the program « Investissements d’Avenir » launched by the French Government. We thank the Ligue Nationale Contre Le Cancer for the fellowship to Y.A.A.

Published
2022

39. Homosalate boosts the release of tumour‐derived extracellular vesicles with protection against anchorage‐loss property

Author

Eleonora Grisard, Nathalie Nevo, Aurianne Lescure, Sebastian Doll, Maxime Corbé, Mabel Jouve, Gregory Lavieu, Alain Joliot, Elaine Del Nery, Lorena Martin‐Jaular, Clotilde Théry, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), BioImaging Cell and Tissue Core Facility (PICT-IBiSA), Institut Curie [Paris], Helmholtz Zentrum München = German Research Center for Environmental Health, Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de sciences cognitives et psycholinguistique (LSCP), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), and Joliot, Alain

Subjects
[SDV] Life Sciences [q-bio], Extracellular Vesicles, Histology, [SDV]Life Sciences [q-bio], Dietary Supplements, Humans, Triple Negative Breast Neoplasms, Cell Biology, Salicylates
Abstract

International audience; Eukaryotic cells, including cancer cells, secrete highly heterogeneous populations of extracellular vesicles (EVs). EVs could have different subcellular origin, composition and functional properties, but tools to distinguish between EV subtypes are scarce. Here, we tagged CD63- or CD9-positive EVs secreted by triple negative breast cancer cells with Nanoluciferase enzyme, to set-up a miniaturized method to quantify secretion of these two EV subtypes directly in the supernatant of cells. We performed a cell-based high-content screening to identify clinically-approved drugs able to affect EV secretion. One of the identified hits is Homosalate, an anti-inflammatory drug found in sunscreens which robustly increased EVs' release. Comparing EVs induced by Homosalate with those induced by Bafilomycin A1, we demonstrate that: (1) the two drugs act on EVs generated in distinct subcellular compartments, and (2) EVs released by Homosalate-, but not by Bafilomycin A1-treated cells enhance resistance to anchorage loss in another recipient epithelial tumour cell line. In conclusion, we identified a new drug modifying EV release and demonstrated that under influence of different drugs, triple negative breast cancer cells release EV subpopulations from different subcellular origins harbouring distinct functional properties.

Published
2022

40. Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearance

Author

Laetitia Fuhrmann, Ivan Bièche, Marie Irondelle, Fabien Reyal, Anne Houdusse, Olena Pylypenko, Stephen J. Weiss, Olivier De Wever, Mathieu Boissan, Anne Vincent-Salomon, Catalina Lodillinsky, Claire Calmel, Ana María Eiján, Philippe Chavrier, Hélène Bonsang-Kitzis, Marie-Lise Lacombe, Sophie Vacher, Xiao Yan Li, Universidad de Buenos Aires [Buenos Aires] (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Institut Curie [Paris], Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Michigan [Ann Arbor], University of Michigan System, Centre de Recherche Saint-Antoine (CR Saint-Antoine), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Ghent University Hospital, Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Neurobiologie des Canaux Ioniques, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de chirurgie, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie [CRSA], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Pylypenko, Olena, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de la Méditerranée - Aix-Marseille 2, Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP]

Subjects
0301 basic medicine, Cancer Research, TUMOR-CELLS, [SDV]Life Sciences [q-bio], Endocytic cycle, PROGRESSION, Matrix metalloproteinase, Extracellular matrix, Dynamin II, Mice, Breast cancer, 0302 clinical medicine, Membrane fission, Cell Movement, Medicine and Health Sciences, Neoplasm Metastasis, skin and connective tissue diseases, Middle Aged, NM23 Nucleoside Diphosphate Kinases, Endocytosis, Extracellular Matrix, [SDV] Life Sciences [q-bio], CARCINOMA IN-SITU, 030220 oncology & carcinogenesis, Female, TRANSITION, DYNAMIN, MIGRATION, Mice, Nude, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, Cell Line, 03 medical and health sciences, Matrix Metalloproteinase 14, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, Animals, Humans, TRAFFICKING, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Metastasis suppressor, Molecular Biology, Neoplasm Staging, Carcinoma in situ, MICROINVASION, Ductal carcinoma, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, Cancer research
Abstract

Membrane Type 1 Matrix Metalloprotease (MT1-MMP) contributes to the invasive progression of breast cancers by degrading extracellular matrix tissues. Nucleoside diphosphate kinase, NME1/NM23-H1, has been identified as a metastasis suppressor; however, its contribution to local invasion in breast cancer is not known. Here, we report that NME1 is up-regulated in ductal carcinoma in situ (DCIS) as compared to normal breast epithelial tissues. NME1 levels drop in microinvasive and invasive components of breast tumor cells relative to synchronous DCIS foci. We find a strong anti-correlation between NME1 and plasma membrane MT1-MMP levels in the invasive components of breast tumors, particularly in aggressive histological grade III and triple-negative breast cancers. Knockout of NME1 accelerates the invasive transition of breast tumors in the intraductal xenograft model. At the mechanistic level, we find that MT1-MMP, NME1 and dynamin-2, a GTPase known to require GTP production by NME1 for its membrane fission activity in the endocytic pathway, interact in clathrin-coated vesicles at the plasma membrane. Loss of NME1 function increases MT1-MMP surface levels by inhibiting endocytic clearance. As a consequence, the ECM degradation and invasive potentials of breast cancer cells are enhanced. This study identifies the down-modulation of NME1 as a potent driver of the in situ-to invasive transition during breast cancer progression.

Published
2021

41. Antigen-Adjuvant Interactions in Vaccines by Taylor Dispersion Analysis: Size Characterization and Binding Parameters

Author

Jérôme Thiebaud, Jean-François Cotte, Laurent Leclercq, Hervé Cottet, Sergio Marco, Marie-Claire Nicolaï, Camille Malburet, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM), Sanofi Pasteur [Marcy-l'Étoile, France], Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), France Miel, Chimie et modélisation pour la biologie du cancer (CMBC), Université Paris-Saclay-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Leclercq, Laurent, and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
[CHIM.POLY] Chemical Sciences/Polymers, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Taylor dispersion, 010402 general chemistry, 01 natural sciences, Analytical Chemistry, [SPI]Engineering Sciences [physics], Immune system, Adjuvants, Immunologic, Vaccine adjuvant, Antigen, [CHIM] Chemical Sciences, medicine, [CHIM]Chemical Sciences, Antigens, ComputingMilieux_MISCELLANEOUS, Vaccines, Chemistry, 010401 analytical chemistry, Electrophoresis, Capillary, 3. Good health, 0104 chemical sciences, [CHIM.POLY]Chemical Sciences/Polymers, Immunology, Adjuvant
Abstract

International audience; Vaccine adjuvants are immunostimulatory substances used to improve and modulate the immune response induced by antigens. A better understanding of the antigen-adjuvant interactions is necessary to develop future effective vaccine. In this study, Taylor dispersion analysis (TDA) was successfully implemented to characterize the interactions between a polymeric adjuvant (poly(acrylic acid), SPA09) and a vaccine antigen in development for the treatment of Staphylococcus aureus. TDA allowed one to rapidly determine both (i) the size of the antigen-adjuvant complexes under physiological conditions and (ii) the percentage of free antigen in the adjuvant/antigen mixture at equilibrium and finally get the interaction parameters (stoichiometry and binding constant). The complex sizes obtained by TDA were compared to the results obtained by transmission electron microscopy, and the binding parameters were compared to results previously obtained by frontal analysis continuous capillary electrophoresis.

Published
2021

42. A role for Dynlt3 in melanosome movement, distribution, acidity and transfer

Author

Alejandro Conde-Perez, Mathilde Di Marco, Sylvie Coscoy, Cédric Delevoye, Florian Rambow, Lionel Larue, Graça Raposo, Zackie Aktary, François Amblard, Ilse Hurbain, Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Ulsan National Institute of Science and Technology (UNIST), and Gestionnaire, Hal Sorbonne Université

Subjects
Male, QH301-705.5, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Skin Pigmentation, Melanocyte, Article, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, DYNLT3, Cytoplasmic dynein complex, medicine, Animals, Biology (General), 030304 developmental biology, Melanosome, Organelles, 0303 health sciences, Melanosomes, Chemistry, Dynein, Wnt signaling pathway, Dyneins, Hedgehog signaling pathway, Cell biology, Mice, Inbred C57BL, Skin diseases, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Melanosome transport, Melanocytes, General Agricultural and Biological Sciences, 030217 neurology & neurosurgery, Biogenesis
Abstract

Skin pigmentation is dependent on cellular processes including melanosome biogenesis, transport, maturation and transfer to keratinocytes. However, how the cells finely control these processes in space and time to ensure proper pigmentation remains unclear. Here, we show that a component of the cytoplasmic dynein complex, Dynlt3, is required for efficient melanosome transport, acidity and transfer. In Mus musculus melanocytes with decreased levels of Dynlt3, pigmented melanosomes undergo a more directional motion, leading to their peripheral location in the cell. Stage IV melanosomes are more acidic, but still heavily pigmented, resulting in a less efficient melanosome transfer. Finally, the level of Dynlt3 is dependent on β-catenin activity, revealing a function of the Wnt/β-catenin signalling pathway during melanocyte and skin pigmentation, by coupling the transport, positioning and acidity of melanosomes required for their transfer., Aktary et al. identify novel roles for the dynein light chain Dynlt3 in melanosome transport, maturation, and transfer to keratinocytes. They also find that the Wnt/βcatenin signalling pathway controls Dynlt3 levels and thus also contributes to the regulation of melanocyte transport and skin pigmentation.

Published
2021

43. The Ways of Actin: Why Tunneling Nanotubes Are Unique Cell Protrusions

Author

Chiara Zurzolo, J. Michael Henderson, Nina Ljubojevic, Trafic membranaire et Pathogénèse - Membrane Traffic and Pathogenesis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Physiologie, physiopathologie et thérapeutique (ED 394), Sorbonne Université (SU), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), N.L. is supported by Sorbonne Université (doctoral grant number 3210/2018), and J.M.H. is supported by a PasteurFoundation Fellowship. Thiswork was supported by grants to C.Z. from Equipe FRM (Fondation pour la RechercheMédicale) 2014 (DEQ 20140329557), Agence Nationale de la Recherche (ANR 16 CE160019-01 NEUROTUNN), UniversitéParis Sciences et Lettres-QLife Institute (ANR-17-CONV-0005 Q-LIFE), and the INCEPTION program-P2I (Investissementd’Avenir grant ANR-16)., ANR-16-CE16-0019,Neurotunn,Role des nanotubes membranaires dans la propagation d'agrégats protéiques impliqués dans les maladie neurodégénératives(2016), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-17-CONV-0005,Q-LIFE,Institut Q-LIFE(2017), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], Cell, Cell Communication, macromolecular substances, Biology, Filamentous actin, tunneling nanotubes, 03 medical and health sciences, 0302 clinical medicine, medicine, actin regulators, Humans, cellular protrusions, Actin, 030304 developmental biology, 0303 health sciences, Nanotubes, actin polymerization, Actin remodeling, Biological Transport, Cell Biology, Actins, Endocytosis, Actin Cytoskeleton, medicine.anatomical_structure, Biophysics, Cell Surface Extensions, filamentous actin, 030217 neurology & neurosurgery
Abstract

International audience; Actin remodeling is at the heart of the response of cells to external or internalstimuli, allowing a variety of membrane protrusions to form. Fifteen years ago,tunneling nanotubes (TNTs) were identified,bringinganoveladditiontothefamily of actin-supported cellular protrusions. Their unique property as conduitsfor cargo transfer between distant cells emphasizes the unique nature of TNTsamong other protrusions. While TNTs in different pathological and physiologicalscenarios have been described, the molecular basis of how TNTs form is not wellunderstood. In this review, we discuss the role of several actin regulators in theformation of TNTs and suggest potential players based on their comparisonwith other actin-based protrusions. New perspectives for discovering a distinctTNT formation pathway would enable us to target them in treating the increasingnumber of TNT-involved pathologies.

Published
2021

44. Episomal HPV16 responsible for aggressive and deadly metastatic anal squamous cell carcinoma evidenced in peripheral blood

Author

Julien Puech, Marie-Laure Lucas, Simon Pernot, Raphael Vernet, David Veyer, Laurence Weiss, Cécile Badoual, Bastien Rance, Nicolas Robillard, Hélène Péré, Laurent Bélec, Sonia Lameiras, Alain Nicolas, Maxime Wack, Juliette Pavie, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Bergonié [Bordeaux], UNICANCER, Hôtel-Dieu, Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Curie [Paris], Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Gestionnaire, Hal Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Science, Context (language use), Virus, Article, Metastasis, Tumour biomarkers, 03 medical and health sciences, 0302 clinical medicine, Biopsy, Carcinoma, Medicine, Humans, Tumour virus infections, Neoplasm Metastasis, Prospective cohort study, Retrospective Studies, Whole genome sequencing, Human papillomavirus 16, Multidisciplinary, medicine.diagnostic_test, business.industry, Papillomavirus Infections, Anal Squamous Cell Carcinoma, virus diseases, Translational research, medicine.disease, Anus Neoplasms, female genital diseases and pregnancy complications, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, Carcinoma, Squamous Cell, business, Biomarkers
Abstract

Archival tissue samples collected longitudinally from a patient who died from HPV16-induced high-grade anal intraepithelial squamous cell carcinoma with vertebral HPV16–positive metastasis were retrospectively analyzed by the Capture-HPV method (Capt-HPV) followed by Next-Generation Sequencing (NGS). Full length nucleotide sequences of the same HPV16 were identified from the initial and second anal biopsy samples, from plasma sample and from vertebral metastasis biopsy. Remarkably, HPV was episomal in each sample. The HPV genome sequence was closest to the HPV16 Qv18158E variant subtype (A1 lineage) exhibiting base substitutions and deletions in 7 and 2 HPV loci, respectively. In conclusion, the powerful Capt-HPV followed by NGS allows evidencing the detailed cartography of tumoral and circulating HPV DNA, giving rise to a unique and unexpected episomal virus molecular status in a context of aggressive carcinoma, underlying the importance of HPV status and its association with clinical features for further prospective studies.

Published
2021

45. The receptor DNGR-1 signals for phagosomal rupture to promote cross-presentation of dead-cell-associated antigens

Author

Santiago Zelenay, Caetano Reis e Sousa, Felix Randow, Hefin Rhys, Neil C. Rogers, Hanna Blees, Oliver Schulz, Michael D. Buck, Cara J. Ellison, Conor M. Henry, Eleanor Childs, David C. Thomas, Venizelos Papayannopoulos, Johnathan Canton, Sebastian Amigorena, Andrés Alloatti, Lucy M. Collinson, Marie-Charlotte Domart, The Francis Crick Institute [London], University of Manchester [Manchester], Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), MRC Laboratory of Molecular Biology [Cambridge, UK] (LMB), University of Cambridge [UK] (CAM)-Medical Research Council, University of Cambridge [UK] (CAM), Institut Curie [Paris], Imperial College London, and AMIGORENA, Sebastian

Subjects
0301 basic medicine, T-Lymphocytes, [SDV]Life Sciences [q-bio], Immunology, Antigen presentation, Ligands, Major histocompatibility complex, Article, Mice, 03 medical and health sciences, Cross-Priming, 0302 clinical medicine, Antigen, Phagosomes, Animals, Humans, Syk Kinase, Immunology and Allergy, Lectins, C-Type, Phosphorylation, Receptors, Immunologic, Antigen Presentation, Cell Death, biology, Chemistry, MHC class I antigen, Histocompatibility Antigens Class I, NADPH Oxidases, Cross-presentation, Dendritic Cells, Acquired immune system, Coculture Techniques, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], HEK293 Cells, RAW 264.7 Cells, 030104 developmental biology, Endocytic vesicle, Receptors, Mitogen, biology.protein, Reactive Oxygen Species, CD8, Signal Transduction, 030215 immunology
Abstract

International audience; Type 1 conventional dendritic (cDC1) cells are necessary for cross-presentation of many viral and tumor antigens to CD8+ T cells. cDC1 cells can be identified in mice and humans by high expression of DNGR-1 (also known as CLEC9A), a receptor that binds dead-cell debris and facilitates XP of corpse-associated antigens. Here, we show that DNGR-1 is a dedicated XP receptor that signals upon ligand engagement to promote phagosomal rupture. This allows escape of phagosomal contents into the cytosol, where they access the endogenous major histocompatibility complex class I antigen processing pathway. The activity of DNGR-1 maps to its signaling domain, which activates SYK and NADPH oxidase to cause phagosomal damage even when spliced into a heterologous receptor and expressed in heterologous cells. Our data reveal the existence of innate immune receptors that couple ligand binding to endocytic vesicle damage to permit MHC class I antigen presentation of exogenous antigens and to regulate adaptive immunity.

Published
2020

46. Immune response profiling of patients with spondyloarthritis reveals signalling networks mediating TNF-blocker function in vivo

Author

Menegatti, Silvia, Guillemot, Vincent, Latis, Eleonora, Yahia-Cherbal, Hanane, Mittermüller, Daniela, Rouilly, Vincent, Mascia, Elena, Rosine, Nicolas, Koturan, Surya, Millot, Gaël, Leloup, Claire, Duffy, Darragh, Gleizes, Aude, Hacein-Bey-Abina, Salima, The Milieu Interieur, Consortium, Sellam, Jérémie, Berenbaum, Francis, Miceli-Richard, Corinne, Dougados, Maxime, Bianchi, Elisabetta, Rogge, Lars, Immunorégulation - Immunoregulation, Institut Pasteur [Paris], Université Sorbonne Paris Cité (USPC), Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Datactix, Immunologie Translationnelle - Translational Immunology lab, Service de Médecine Interne - Immunologie Clinique [AP-HP Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Institut de Chimie du CNRS (INC)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Service de rhumatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Equipe 2 : ECSTRA - Epidémiologie Clinique, STatistique, pour la Recherche en Santé (CRESS - U1153), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), SM was a scholar of the Pasteur-Paris University (PPU) International PhD programme and supported by a grant from the Fondation pour la Recherche Médicale. EL was supported by a fellowship from the Université Paris Diderot. This study was Institut Pasteur, the French Government’s Investissement d’Avenir Programme, Laboratoire d’Excellence 'Milieu Intérieur' (ANR-10-LABX-69-01), FOREUM Foundation for Research in Rheumatology, the Fondation Arthritis, MSD Avenir (Project iCARE-SpA), a Bourse Passerelle from Pfizer., Milieu Intérieur Consortium: Laurent Abel, Andres Alcover, Hugues Aschard, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Ivo Gomperts-Boneca, Milena Hasan, Serge Hercberg, Olivier Lantz, Hugo Mouquet, Etienne Patin, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert, Mathilde Trouvier, Marie-Noëlle Ungeheuer, Darragh Duffy, Matthew L. Albert, Lluis Quintana-Murci., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris] (IP), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
rheumatoid arthritis, 0301 basic medicine, Chemokine, anti-TNF therapy, [SDV]Life Sciences [q-bio], tumor necrosis factor inhibitors, immune system diseases, Immunology, Inflammation, General Biochemistry, Genetics and Molecular Biology, TNF inhibitors, 03 medical and health sciences, 0302 clinical medicine, Immune system, Rheumatology, Immunity, Spondylarthritis, Spondyloarthritis, Humans, Immunology and Allergy, Medicine, Spondylitis, Ankylosing, 030203 arthritis & rheumatology, Innate immune system, biology, Tumor Necrosis Factor-alpha, business.industry, Interleukin, spondylitis, Chemotaxis, 3. Good health, chronic inflammatory diseases, ankylosing, 030104 developmental biology, biological therapy, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Tumor necrosis factor alpha, medicine.symptom, business
Abstract

ObjectivesAntitumour necrosis factor (TNF) therapy has revolutionised treatment of several chronic inflammatory diseases, including spondyloarthritis (SpA). However, TNF inhibitors (TNFi) are not effective in all patients and the biological basis for treatment failure remains unknown. We have analysed induced immune responses to define the mechanism of action of TNF blockers in SpA and to identify immunological correlates of responsiveness to TNFi.MethodsImmune responses to microbial and pathway-specific stimuli were analysed in peripheral blood samples from 80 patients with axial SpA before and after TNFi treatment, using highly standardised whole-blood stimulation assays. Cytokines and chemokines were measured in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, and gene expression was monitored using nCounter assays.ResultsAnti-TNF therapy induced profound changes in patients’ innate immune responses. TNFi action was selective, and had only minor effects on Th1/Th17 immunity. Modular transcriptional repertoire analysis identified prostaglandin E2 synthesis and signalling, leucocyte recirculation, macrophage polarisation, dectin and interleukin (IL)-1 signalling, as well as the nuclear factor kappa B (NF-kB) transcription factor family as key pathways targeted by TNF blockers in vivo. Analysis of induced immune responses before treatment initiation revealed that expression of molecules associated with leucocyte adhesion and invasion, chemotaxis and IL-1 signalling are correlated with therapeutic responses to anti-TNF.ConclusionsWe show that TNFi target multiple immune cell pathways that cooperate to resolve inflammation. We propose that immune response profiling provides new insight into the biology of TNF-blocker action in patients and can identify signalling pathways associated with therapeutic responses to biological therapies.

Published
2020

47. Digital phenotyping in young breast cancer patients treated with neoadjuvant chemotherapy (the NeoFit Trial): protocol for a national, multicenter single-arm trial

Author

Lidia Delrieu, Anne-Sophie Hamy, Florence Coussy, Amyn Kassara, Bernard Asselain, Juliana Antero, Paul De Villèle, Elise Dumas, Nicolas Forstmann, Julien Guérin, Judicael Hotton, Christelle Jouannaud, Maud Milder, Armand Leopold, Adrien Sedeaud, Pauline Soibinet, Jean-François Toussaint, Vincent Vercamer, Enora Laas, Fabien Reyal, Residual Tumor & Response to Treatment Laboratory [Paris] (RT2Lab), Translational Research Department [Paris], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncologie Médicale [Institut Curie, Paris], Institut Curie [Paris], Groupe d'Investigateurs Nationaux pour l'Étude des Cancers de l'Ovaire et du sein [Paris] (GINECO), Institut de recherche biomédicale et d’épidémiologie du sport (IRMES - URP_7329), Institut national du sport, de l'expertise et de la performance (INSEP)-Université Paris Cité (UPCité), Withings [Issy-les-Moulineaux] (W), Institut national du sport, de l'expertise et de la performance (INSEP), CRLCC Jean Godinot, Centre d'Investigation en Médecine du sport (CIMS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu, Département d'Oncologie Chirurgicale [Institut Curie], and Malbec, Odile

Subjects
Male, Cancer Research, Prevention, [SDV]Life Sciences [q-bio], Breast Neoplasms, Digital, Neoadjuvant Therapy, [SDV] Life Sciences [q-bio], Oncology, Antineoplastic Combined Chemotherapy Protocols, Quality of Life, Genetics, Humans, Multicenter Studies as Topic, Female, Prospective Studies, Neoadjuvant, Activity trackers
Abstract

Background Breast cancer (BC) has particular characteristics in young women, with diagnosis at more advanced stages, a poorer prognosis and highly aggressive tumors. In NeoFit, we will use an activity tracker to identify and describe various digital profiles (heart rate, physical activity, and sleep patterns) in women below the age of 45 years on neoadjuvant chemotherapy for BC. Methods NeoFit is a prospective, national, multicenter, single-arm open-label study. It will include 300 women below the age of 45 years treated with neoadjuvant chemotherapy for BC. Participants will be asked to wear a Withing Steel HR activity tracker round the clock for 12 months. The principal assessments will be performed at baseline, at the end of neoadjuvant chemotherapy and at 12 months. We will evaluate clinical parameters, such as toxicity and the efficacy of chemotherapy, together with quality of life, fatigue, and parameters relating to lifestyle and physical activity. The women will complete REDCap form questionnaires via a secure internet link. Discussion In this study, the use of an activity tracker will enable us to visualize changes in the lifestyle of young women on neoadjuvant chemotherapy for BC, over the course of a one-year period. This exploratory study will provide crucial insight into the digital phenotypes of young BC patients on neoadjuvant chemotherapy and the relationship between these phenotypes and the toxicity and efficacy of treatment. This trial will pave the way for interventional studies involving sleep and physical activity interventions. Trial registration Clinicaltrials.gov identifier: NCT05011721. Registration date: 18/08/2021.

Published
2022

48. A comparison of Sars-Cov-2 vaccine platforms: the CoviCompare project

Author

Diana Molino, Christine Durier, Anne Radenne, Corinne Desaint, Jacques Ropers, Soizic Courcier, Louis Victorien Vieillard, Claire Rekacewicz, Beatrice Parfait, Victor Appay, Frédéric Batteux, Emmanuel Barillot, Michel Cogné, Béhazine Combadière, Christiane S. Eberhardt, Guy Gorochov, Philippe Hupé, Laetitia Ninove, Stéphane Paul, Isabelle Pellegrin, Sylvie van der Werf, Maeva Lefebvre, Elisabeth Botelho-Nevers, Inmaculada Ortega-Perez, Marie Jaspard, Samba Sow, Jean Daniel Lelièvre, Xavier de Lamballerie, Marie Paule Kieny, Eric Tartour, Odile Launay, CIC Cochin Pasteur (CIC 1417), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), F-CRIN, Innovative clinical research network in vaccinology (I-REIVAC), Essais Thérapeutiques et Maladies Infectieuses, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Faculté de médecine [Genève], Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD), Physiologie cellulaire des régulations hormonale, nutritionnelles et pharmacologiques (UMR-S-530), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Alliance for International medical Action (ALIMA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre pour le Développement des Vaccins [Mali], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biochimie des Lipides, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Ministere des Solidarites et de la Sante, Ministere de l'Enseignement Superieur, de la Recherche et de l'Innovation, Coalition for Epidemic Preparedness Innovations (CEPI), ANRS \Emerging Infectious Diseases, ANR-20-COV3-0004,CoMemRep,Caractérisation des complexes de réplication associés à la membrane du SARS CoV 2(2020), Unité de Recherche Clinique des hôpitaux Pitié-Salpêtrière – Charles Foix [CHU Pitié Salpêtrière] (URC PSL-CFX), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Direction de la Recherche Clinique et de l'Innovation [AP-HP] (DRCI), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Chard-Hutchinson, Xavier, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
[SDV] Life Sciences [q-bio], COVID-19 Vaccines, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, SARS-CoV-2, [SDV]Life Sciences [q-bio], Spike Glycoprotein, Coronavirus, COVID-19, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, General Medicine, General Biochemistry, Genetics and Molecular Biology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2022

49. Synthetic reconstruction of the hunchback promoter specifies the role of Bicoid, Zelda and Hunchback in the dynamics of its transcription

Author

Fernandes, Gonçalo, Tran, Huy, Andrieu, Maxime, Diaw, Youssoupha, Perez Romero, Carmina, Fradin, Cécile, Coppey, Mathieu, Walczak, Aleksandra M, Dostatni, Nathalie, Tampere University, BioMediTech, Dynamique du noyau [Institut Curie], Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Physique Statistique et Inférence pour la Biologie, Laboratoire de physique de l'ENS - ENS Paris (LPENS), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Département de Physique de l'ENS-PSL, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Département de Physique de l'ENS-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Fondation ARC pour la Recherche sur le Cancer (DOC42021020003330), Fondation ARC pour la Recherche sur le Cancer (PJA20191209543), Natural Sciences and Engineering Research Council of Canada (RGPIN-2015-06362), Fondation ARC pour la Recherche sur le Cancer (PJA20151203341), Institut Curie, Agence Nationale de la Recherche (PSL IDEX Mesoscopic Biology), ANR-19-CE13-0025,FIREFLY,Bruit et robustesse en aval d'un gradient morphogénétique : approche quantitative par imagerie de la transcription dans les embryons vivants(2019), ANR-11-LABX-0044,DEEP,Développement, Epigénèse, Epigénétique et potentiel de vie(2011), and European Project: 666003,H2020,H2020-MSCA-COFUND-2014,IC-3i-PhD(2016)

Subjects
body regions, animal structures, General Immunology and Microbiology, General Neuroscience, [SDV]Life Sciences [q-bio], fungi, embryonic structures, General Medicine, 3111 Biomedicine, General Biochemistry, Genetics and Molecular Biology
Abstract

For over 40 years, the Bicoid-hunchback (Bcd-hb) system in the fruit fly embryo has been used as a model to study how positional information in morphogen concentration gradients is robustly translated into step-like responses. A body of quantitative comparisons between theory and experiment have since questioned the initial paradigm that the sharp hb transcription pattern emerges solely from diffusive biochemical interactions between the Bicoid transcription factor and the gene promoter region. Several alternative mechanisms have been proposed, such as additional sources of positional information, positive feedback from Hb proteins or out-of-equilibrium transcription activation. By using the MS2-MCP RNA-tagging system and analysing in real time, the transcription dynamics of synthetic reporters for Bicoid and/or its two partners Zelda and Hunchback, we show that all the early hb expression pattern features and temporal dynamics are compatible with an equilibrium model with a short decay length Bicoid activity gradient as a sole source of positional information. Meanwhile, Bicoid’s partners speed-up the process by different means: Zelda lowers the Bicoid concentration threshold required for transcriptional activation while Hunchback reduces burstiness and increases the polymerase firing rate.

Published
2022

50. Rectified random cell motility as a mechanism for embryo elongation

Author

Ido Regev, Karine Guevorkian, Anupam Gupta, Olivier Pourquié, L. Mahadevan, Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), Harvard University, Alexandre Yersin Department of Solar Energy and Environmental Physics (YDSEEP), The Jacob Blaustein Institutes for Desert Research (BIDR), Ben-Gurion University of the Negev (BGU)-Ben-Gurion University of the Negev (BGU), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Indian Institute of Technology [Hyderabad] (IIT Hyderabad), Brigham and Women’s Hospital [Boston, MA], Harvard Medical School [Boston] (HMS), 1R01HD097068, ANR-14-CE32-0009,ElongMech,Mécanique de l'élongation embryonnaire chez les vertébrés(2014), European Project, Harvard University [Cambridge], Guevorkian, Karine, Appel à projets générique - Mécanique de l'élongation embryonnaire chez les vertébrés - - ElongMech2014 - ANR-14-CE32-0009 - Appel à projets générique - VALID, and RGP0051/ 2012 - INCOMING

Subjects
[PHYS]Physics [physics], Embryo elongation, [SDV]Life Sciences [q-bio], Chick Embryo, Rectified motility, Embryo, Mammalian, [PHYS] Physics [physics], [SDV] Life Sciences [q-bio], Mesoderm, Chick morphogenesis, Tissue expansion, Cell Movement, Vertebrates, Animals, Molecular Biology, Developmental Biology, Research Article, Signal Transduction
Abstract

The body of vertebrate embryos forms by posterior elongation from a terminal growth zone called the tail bud. The tail bud is a source of highly motile cells that eventually constitute the presomitic mesoderm (PSM), a tissue that plays an important role in elongation movements. PSM cells establish an anterior-posterior cell motility gradient that parallels a gradient associated with the degradation of a specific cellular signal (FGF) known to be implicated in cell motility. Here, we combine the electroporation of fluorescent reporters in the PSM with time-lapse imaging in the chicken embryo to quantify cell diffusive movements along the motility gradient. We show that a simple microscopic model for random cell motility induced by FGF activity along with geometric confinement leads to rectified tissue elongation consistent with our observations. A continuum analog of the microscopic model leads to a macroscopic mechano-chemical model for tissue extension that couples FGF activity-induced cell motility and tissue rheology, and is consistent with the experimentally observed speed and extent of elongation. Together, our experimental observations and theoretical models explain how the continuous addition of cells at the tail bud combined with lateral confinement can be converted into oriented movement and drive body elongation.

Published
2022

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