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1. Gallocin A, an atypical two-peptide bacteriocin with intramolecular disulfide bonds required for activity

Author: Alexis Proutière, Laurence du Merle, Marta Garcia-Lopez, Corentin Léger, Alexis Voegele, Alexandre Chenal, Antony Harrington, Yftah Tal-Gan, Thomas Cokelaer, Patrick Trieu-Cuot, Shaynoor Dramsi, Biologie des Bactéries pathogènes à Gram-positif - Biology of Gram-Positive Pathogens, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biochimie des Interactions Macromoléculaires / Biochemistry of Macromolecular Interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Nevada [Reno], Biomics (plateforme technologique), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, This study has been funded by the Institut National Contre le Cancer (INCA) PLBIO 16-025, attributed to S.D., and by the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases (grant no. ANR-10-LABX-62-IBEID)'. This study was also funded by the National Science Foundation (NSF, no. CHE-1808370 to Y.T.-G.)., and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
Subjects: Microbiology (medical), Streptococcus gallolyticus, General Immunology and Microbiology, Ecology, immunity peptide, Physiology, [SDV]Life Sciences [q-bio], Cell Biology, constitute, class IIb bacteriocin, bacteriocins, antimicrobial peptides, 3-dimensional structure, Infectious Diseases, 2 peptides, Genetics, disulfide bond, mutation
Abstract: Streptococcus gallolyticus subsp. gallolyticus (SGG) is an opportunistic gut pathogen associated with colorectal cancer. We previously showed that colonization of the murine colon by SGG in tumoral conditions was strongly enhanced by the production of gallocin A, a two-peptide bacteriocin. Here, we aimed to characterize the mechanisms of its action and resistance. Using a genetic approach, we demonstrated that gallocin A is composed of two peptides, GllA1 and GllA2, which are inactive alone and act together to kill "target" bacteria. We showed that gallocin A can kill phylogenetically close relatives of the pathogen. Importantly, we demonstrated that gallocin A peptides can insert themselves into membranes and permeabilize lipid bilayer vesicles. Next, we showed that the third gene of the gallocin A operon, gip, is necessary and sufficient to confer immunity to gallocin A. Structural modeling of GllA1 and GllA2 mature peptides suggested that both peptides form alpha-helical hairpins stabilized by intramolecular disulfide bridges. The presence of a disulfide bond in GllA1 and GllA2 was confirmed experimentally. Addition of disulfide-reducing agents abrogated gallocin A activity. Likewise, deletion of a gene encoding a surface protein with a thioredoxin-like domain impaired the ability of gallocin A to kill Enterococcus faecalis. Structural modeling of GIP revealed a hairpin-like structure strongly resembling those of the GllA1 and GllA2 mature peptides, suggesting a mechanism of immunity by competition with GllA1/2. Finally, identification of other class IIb bacteriocins exhibiting a similar alpha-helical hairpin fold stabilized with an intramolecular disulfide bridge suggests the existence of a new subclass of class IIb bacteriocins.IMPORTANCE Streptococcus gallolyticus subsp. gallolyticus (SGG), previously named Streptococcus bovis biotype I, is an opportunistic pathogen responsible for invasive infections (septicemia, endocarditis) in elderly people and is often associated with colon tumors. SGG is one of the first bacteria to be associated with the occurrence of colorectal cancer in humans. Previously, we showed that tumor-associated conditions in the colon provide SGG with an ideal environment to proliferate at the expense of phylogenetically and metabolically closely related commensal bacteria such as enterococci (1). SGG takes advantage of CRC-associated conditions to outcompete and substitute commensal members of the gut microbiota using a specific bacteriocin named gallocin, recently renamed gallocin A following the discovery of gallocin D in a peculiar SGG isolate. Here, we showed that gallocin A is a two-peptide bacteriocin and that both GllA1 and GllA2 peptides are required for antimicrobial activity. Gallocin A was shown to permeabilize bacterial membranes and kill phylogenetically closely related bacteria such as most streptococci, lactococci, and enterococci, probably through membrane pore formation. GllA1 and GllA2 secreted peptides are unusually long (42 and 60 amino acids long) and have very few charged amino acids compared to well-known class IIb bacteriocins. In silico modeling revealed that both GllA1 and GllA2 exhibit a similar hairpin-like conformation stabilized by an intramolecular disulfide bond. We also showed that the GIP immunity peptide forms a hairpin-like structure similar to GllA1/GllA2. Thus, we hypothesize that GIP blocks the formation of the GllA1/GllA2 complex by interacting with GllA1 or GllA2., Gallocin A may constitute the first class IIb bacteriocin which displays disulfide bridges important for its structure and activity and might be the founding member of a subtype of class IIb bacteriocins., Streptococcus gallolyticus subsp. gallolyticus (SGG), previously named Streptococcus bovis biotype I, is an opportunistic pathogen responsible for invasive infections (septicemia, endocarditis) in elderly people and is often associated with colon tumors. SGG is one of the first bacteria to be associated with the occurrence of colorectal cancer in humans. Previously, we showed that tumor-associated conditions in the colon provide SGG with an ideal environment to proliferate at the expense of phylogenetically and metabolically closely related commensal bacteria such as enterococci (1). SGG takes advantage of CRC-associated conditions to outcompete and substitute commensal members of the gut microbiota using a specific bacteriocin named gallocin, recently renamed gallocin A following the discovery of gallocin D in a peculiar SGG isolate.
Published: 2022
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2. Targeting of MCL-1 in breast cancer-associated fibroblasts reverses their myofibroblastic phenotype and pro-invasive properties

Author: Thomas L. Bonneaud, Chloé C. Lefebvre, Lisa Nocquet, Agnes Basseville, Julie Roul, Hugo Weber, Mario Campone, Philippe P. Juin, Frédérique Souazé, Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-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), SIRIC ILIAD [Angers, Nantes], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, CRLCC René Gauducheau, Ligue contre le cancer (CD53, CD22, CD44), SIRIC ILIAD, INCa-DGOS Inserm-12558, and INCa-PLBio 16086, and Souazé, Frédérique
Subjects: Cancer Research, [SDV]Life Sciences [q-bio], Immunology, Breast Neoplasms, Cell Biology, Apoptosis / drug effects, Mitochondria dynamic, [SDV] Life Sciences [q-bio], Cellular and Molecular Neuroscience, Phenotype, Breast cancer, Cancer associated fibroblasts CAFs, Cancer-Associated Fibroblasts, Humans, Myeloid Cell Leukemia Sequence 1 Protein, Female, MCL-1, Ecosystem
Abstract: Cancer-associated fibroblasts (CAF) are a major cellular component of epithelial tumors. In breast cancers in particular these stromal cells have numerous tumorigenic effects in part due to their acquisition of a myofibroblastic phenotype. Breast CAFs (bCAFs) typically express MCL-1. We show here that pharmacological inhibition or knock down of this regulator of mitochondrial integrity in primary bCAFs directly derived from human samples mitigates myofibroblastic features. This decreases expression of genes involved in actomyosin organization and contractility (associated with a cytoplasmic retention of the transcriptional regulator, yes-associated protein—YAP) and decreases bCAFs ability to promote cancer cells invasion in 3D coculture assays. Our findings underscore the usefulness of targeting MCL-1 in breast cancer ecosystems, not only to favor death of cancer cells but also to counteract the tumorigenic activation of fibroblasts with which they co-evolve. Mechanistically, pharmacological inhibition of MCL-1 with a specific BH3 mimetic promotes mitochondrial fragmentation in bCAFs. Inhibition of the mitochondrial fission activity of DRP-1, which interacts with MCL-1 upon BH3 mimetic treatment, allows the maintenance of the myofibroblastic phenotype of bCAFs.
Published: 2022
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3. Internalization study of nanosized zeolite crystals in human glioblastoma cells

Author: Charly Helaine, Hayriye Özçelik, Sarah Komaty, Abdallah Amedlous, Sajjad Ghojavand, Didier Goux, Richard Retoux, Svetlana Mintova, Samuel Valable, Imagerie et Stratégies Thérapeutiques pour les Cancers et Tissus cérébraux (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire catalyse et spectrochimie (LCS), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Interactions Cellules Organismes Environnement (ICORE), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire de cristallographie et sciences des matériaux (CRISMAT), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), and INCA PLBIO 11699
Subjects: Colloidal suspension, Cell uptake, Nanosized zeolite, Cytotoxicity, [SDV]Life Sciences [q-bio], Surfaces and Interfaces, General Medicine, Faujasite, Oxygen, Colloid and Surface Chemistry, Zeolites, [CHIM]Chemical Sciences, Humans, Tissue Distribution, Physical and Theoretical Chemistry, Glioblastoma, Hypoxia, Biotechnology
Abstract: CERVOXY; International audience; While the use of nanozeolites for cancer treatment holds a great promise, it also requires a better understanding of the interaction between the zeolite nanoparticles and cancer cells and notably their internalization and biodistribution. It is particularly important in situation of hypoxia, a very common situations in aggressive cancers, which may change the energetic processes required for cellular uptake. Herein, we studied, in vitro, the kinetics of the internalization process and the intracellular localization of nanosized zeolite X (FAU-X) into glioblastoma cells. In normoxic conditions, scanning electron microscopy (SEM) showed a rapid cell membrane adhesion of zeolite nanoparticles (< 5 min following application in the cell medium), occurring before an energy-dependent uptake which appeared between 1 h and 4 h. Additionally, transmission electron microscopy (TEM) and flow cytometry analyzes, confirmed that the zeolite nanoparticles accumulate over time into the cytoplasm and were mostly located into vesicles visible at least up to 6 days. Interestingly, the uptake of zeolite nanoparticles was found to be dependent on oxygen concentration, i.e. an increase in internalization in severe hypoxia (0.2 % of O2) was observed. No toxicity of zeolite FAU-X nanoparticles was detected after 24 h and 72 h. The results clearly showed that the nanosized zeolites crystals were rapidly internalized via energy-requiring mechanism by cancer cells and even more in the hypoxic conditions. Once the zeolite nanoparticles were internalized into cells, they appeared to be safe and stable and therefore, they are envisioned to be used as carrier of various compounds to target cancer cells.
Published: 2022
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4. Pharmacological Targeting of IRE1 in Cancer

Author: Dimitrios Doultsinos, Eric Chevet, Antonio Carlesso, Diana Pelizzari Raymundo, Xavier Guillory, Leif A. Eriksson, Jonchère, Laurent, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of Gothenburg (GU), This work was funded by grants from Institut National du Cancer (INCa PLBIO), Fondation pour la Recherche Médicale (FRM, équipe labellisée 2018), ERANET , and Agence Nationale de la Recherche (ERAAT) to E.C., EU H2020 MSCA ITN-675448 (TRAINERS), and MSCA RISE-734749 (INSPIRED) provided grants to L.A.E. and E.C. D.P.R. was funded by INSERM (LA VANNETAISE). X.G. was funded by a post-doctoral fellowship from Fondation ARC , and D.D. and A.C. were MSCA ITN fellows (TRAINERS)., Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)
Subjects: 0301 basic medicine, Cancer Research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Context (language use), IRE1, Protein Serine-Threonine Kinases, Inositol-requiring enzyme 1, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Allosteric Regulation, Protein Domains, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Endoribonucleases, inhibitors, Humans, Medicine, Mode of action, Protein Kinase Inhibitors, activators, business.industry, Cancer, unfolded protein response, Endoplasmic Reticulum Stress, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, endoplasmic reticulum, 030104 developmental biology, Oncology, Protein kinase domain, 030220 oncology & carcinogenesis, Proteostasis, Unfolded protein response, business, Signal Transduction
Abstract: International audience; IRE1α (inositol requiring enzyme 1 alpha) is one of the main transducers of the unfolded protein response (UPR). IRE1α plays instrumental protumoral roles in several cancers, and high IRE1α activity has been associated with poorer prognoses. In this context, IRE1α has been identified as a potentially relevant therapeutic target. Pharmacological inhibition of IRE1α activity can be achieved by targeting either the kinase domain or the RNase domain. Herein, the recent advances in IRE1α pharmacological targeting is summarized. We describe the identification and optimization of IRE1α inhibitors as well as their mode of action and limitations as anticancer drugs. The potential pitfalls and challenges that could be faced in the clinic, and the opportunities that IRE1α modulating strategies may present are discussed.
Published: 2020
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5. A cell-based system combined with flow cytometry to evaluate antibody responses against SARS-CoV-2 transmembrane proteins in patients with COVID-19

Author: Sophie Martin, Gwénaële Jégou, Aurore Nicolas, Matthieu Le Gallo, Éric Chevet, Florence Godey, Tony Avril, Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), CHU Pontchaillou [Rennes], Centre de Ressources Biologiques Santé (CRB Santé), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), This work was funded by grants from INSERM, Institut National du Cancer (INCa PLBIO), Fondation pour la Recherche Médicale (FRM, DEQ20180339169) to E.C. and from la Ligue contre le cancer (comité 35, 56, et 85) to T.A., and Jonchère, Laurent
Subjects: Microbiology, General Immunology and Microbiology, Health Sciences, SARS-CoV-2, General Neuroscience, COVID-19, Membrane Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antibody, Flow Cytometry, Cell Biology, General Biochemistry, Genetics and Molecular Biology, HEK293 Cells, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antibody Formation, Spike Glycoprotein, Coronavirus, Humans, Flow Cytometry/Mass Cytometry, Cell-based Assays, Molecular Biology
Abstract: International audience; This protocol describes a flow cytometry approach to evaluate antibody responses against SARS-CoV-2 transmembrane proteins in COVID-19-positive patient sera samples without the need of specific laboratory facilities for viral infection. We developed a human-cell-based system using spike-expressing HEK293T cells that mimics membrane insertion and N-glycosylation of viral integral membrane proteins in host cells. This assay represents a powerful tool to test antibody responses against SARS-CoV-2 variants and vaccine effectiveness. For complete details on the use and execution of this protocol, please refer to Martin et al. (2021).
Published: 2022
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6. MMP7 cleavage of amino-terminal CD95 death receptor switches signaling toward non-apoptotic pathways

Author: Shoji F. Kenji, Keerthi Kurma, Brigitte Collet, Christelle Oblet, Laure Debure, Carmelo Di Primo, Laëtitia Minder, Franck Vérité, Yannic Danger, Mickael Jean, Aubin Penna, Nicolas Levoin, Patrick Legembre, Jonchère, Laurent, Jeunes Chercheuses et Jeunes Chercheurs - Vivre ou Mourir : Le calcium comme point de contrôle déterminant le destin d'une cellule suite à la stimulation des récepteurs de mort. - - Ca-DoS2012 - ANR-12-JSV2-0004 - JC - VALID, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-OmégaHealth (ΩHealth), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), CRLCC Eugène Marquis (CRLCC), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Imagerie Moléculaire et Nanobiotechnologies - Institut Européen de Chimie et Biologie (IECB), Université Sciences et Technologies - Bordeaux 1 (UB)-Centre National de la Recherche Scientifique (CNRS), Soutien à la Recherche de l'Institut Européen de Chimie Biologique, Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Européen de Chimie et de Biologie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang Bretagne, EFS, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Bioprojet-Biotech, This work was supported by INCa PLBIO, Ligue Contre le Cancer, Fondation de France (Price Jean Valade), Fondation Ruban Rose, ANR PRCE, ANR-12-JSV2-0004-001 and Rennes Métropole AIS grants. With also financial support from ITMO Cancer of Aviesan within the framework of the 2021-2030 Cancer Control Strategy, on funds administered by Inserm. We thank Avril T. (Centre Eugène Marquis, Rennes) for technical assistance with cytometry analysis of peripheral blood cells. The Biacore T200 instrument used in the work was acquired with the support of the Conseil Régional d’Aquitaine, the GIS-IBiSA, and the Cellule Hôtels à Projets of the CNRS., and ANR-12-JSV2-0004,Ca-DoS,Vivre ou Mourir : Le calcium comme point de contrôle déterminant le destin d'une cellule suite à la stimulation des récepteurs de mort.(2012)
Subjects: Cancer Research, Cellular and Molecular Neuroscience, Phosphatidylinositol 3-Kinases, [SDV.CAN] Life Sciences [q-bio]/Cancer, Leucine, Matrix Metalloproteinase 7, Immunology, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Biology, fas Receptor, Protein Sorting Signals, Arginine
Abstract: CD95 is a death receptor that can promote oncogenesis through molecular mechanisms that are not fully elucidated. Although the mature CD95 membrane receptor is considered to start with the arginine at position 17 after elimination of the signal peptide, this receptor can also be cleaved by MMP7 upstream of its leucine at position 37. This post-translational modification occurs in cancer cells but also in normal cells such as peripheral blood leukocytes. The non-cleaved CD95 amino-terminal region consists in a disordered domain and its in silico reconstitution suggests that it might contribute to receptor aggregation and thereby, regulate the downstream death signaling pathways. In agreement with this molecular modeling analysis, the comparison of CD95-deficient cells reconstituted with full-length or N-terminally truncated CD95 reveals that the loss of the amino-terminal region of CD95 impairs the initial steps of the apoptotic signal while favoring the induction of pro-survival signals, including the PI3K and MAPK pathways.
Published: 2022
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7. Role of metalloproteases in the CD95 signaling pathways

Author: Laurent Devel, Nicolas Guedeney, Sarah Bregant, Animesh Chowdhury, Mickael Jean, Patrick Legembre, Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-OmégaHealth (ΩHealth), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), INCa PLBIO [ANR-17-CE15-0027], ANR PRCE, ITMO Cancer of Aviesan within the framework of the 2021-2030 Cancer Control Strategy, [PLBIO 2018-132], and ANR-17-CE15-0027,FASILE,Impact du CD95L, dans la dysfonction des lymphocytes T exprimant l'IL-17 au cours du lupus(2017)
Subjects: MMP, inflammation, Immunology, Immunology and Allergy, ADAM, CD95L, cancer, [CHIM]Chemical Sciences, cleavage
Abstract: International audience; CD95L (also known as FasL or CD178) is a member of the tumor necrosis family (TNF) superfamily. Although this transmembrane ligand has been mainly considered as a potent apoptotic inducer in CD95 (Fas)-expressing cells, more recent studies pointed out its role in the implementation of non-apoptotic signals. Accordingly, this ligand has been associated with the aggravation of inflammation in different auto-immune disorders and in the metastatic occurrence in different cancers. Although it remains to decipher all key factors involved in the ambivalent role of this ligand, accumulating clues suggest that while the membrane bound CD95L triggers apoptosis, its soluble counterpart generated by metalloprotease-driven cleavage is responsible for its non-apoptotic functions. Nonetheless, the metalloproteases (MMPs and ADAMs) involved in the CD95L shedding, the cleavage sites and the different stoichiometries and functions of the soluble CD95L remain to be elucidated. To better understand how soluble CD95L triggers signaling pathways from apoptosis to inflammation or cell migration, we propose herein to summarize the different metalloproteases that have been described to be able to shed CD95L, their cleavage sites and the biological functions associated with the released ligands. Based on these new findings, the development of CD95/CD95L-targeting therapeutics is also discussed.
Published: 2022
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8. Sensor dimer disruption as a new mode of action to block the IRE1-mediated unfolded protein response

Author: Amarasinghe, Kosala N, Pelizzari-Raymundo, Diana, Carlesso, Antonio, Chevet, Eric, Eriksson, Leif A, Jalil Mahdizadeh, Sayyed, University of Gothenburg (GU), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Università della Svizzera italiana = University of Italian Switzerland (USI), This research was funded by the EU’s Horizon 2020 research and innovation programme under the MSCA-RISE programme 734749 (INSPIRED) (LAE, AC, EC), Institut National du Cancer (INCa PLBio), Fondation pour la Recherche Médicale (FRM, DEQ20180339169) and eRARE (Agence Nationale de la Recherche, ERAAT) to EC. Funding from the Vinnova Seal-of-Excellence programme 2019-02205 (CaTheDRA) is gratefully acknowledged (SJM). Elisabeth and Alfred Ahlqvists Foundation (AC), the Faculty of Science at the University of Gothenburg and the Swedish Science Research Council (VR, grant number 2019-3684) (LAE) are also gratefully acknowledged for funding. The authors thank the Swedish National Infrastructure for Computing for generous allocations of computing time at supercomputing centers C3SE and PDC, in part funded by the Swedish Research Council through grant agreement no. 2018-05973. DPR was funded by a grant from Region Bretagne., ANR-17-RAR3-0003,ERAAT,Enhancing Endoplasmic Reticulum Proteostasis to Rescue Alpha1 Antitrypsin Deficiency(2017), Jonchère, Laurent, and Enhancing Endoplasmic Reticulum Proteostasis to Rescue Alpha1 Antitrypsin Deficiency - - ERAAT2017 - ANR-17-RAR3-0003 - E-RARE - VALID
Subjects: MD simulations, Peptide docking, Dimer disruptor, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, IRE1α, UPR, FDA approved drugs
Abstract: International audience; The unfolded protein response (UPR) is activated to cope with an accumulation of improperly folded proteins in the Endoplasmic reticulum (ER). The Inositol requiring enzyme 1α (IRE1α) is the most evolutionary conserved transducer of the UPR. Activated IRE1 forms ’back-to-back’-dimers that enables the unconventional splicing of X-box Binding Protein 1 (XBP1) mRNA. The spliced XBP1 (XBP1s) mRNA is translated into a transcription factor controlling the expression of UPR target genes. Herein, we report a detailed in silico screening specifically targeting for the first time the dimer interface at the IRE1 RNase region. Using the database of FDA approved drugs, we identified four compounds (neomycin, pemetrexed, quercitrin and rutin) that were able to bind to and distort IRE1 RNase cavity. The activity of the compounds on IRE1 phosphorylation was evaluated in HEK293T cells and on IRE1 RNase activity using an in vitro fluorescence assay. These analyzes revealed sub-micromolar IC(50) values. The current study reveals a new and unique mode of action to target and block the IRE1-mediated UPR signaling, whereby we may avoid problems associated with selectivity occurring when targeting the IRE1 kinase pocket as well as the inherent reactivity of covalent inhibitors targeting the RNase pocket.
Published: 2022
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9. Structural and molecular bases to IRE1 activity modulation

Author: Nicolas Gouault, Timothy Langlais, Xavier Guillory, Eric Chevet, François Carreaux, Diana Pelizzari-Raymundo, Leif A. Eriksson, Sayyed Jalil Mahdizadeh, Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), University of Gothenburg (GU), Institut National du Cancer (INCa PLBIO) Institut National du Cancer (INCA) France, Fondation pour la Recherche Medicale (FRM) Fondation pour la Recherche Medicale [DEQ20180339169], ERANET, Agence Nationale de la Recherche (ERAAT) French National Research Agency (ANR), EU European Commission [H2020 MSCA ITN-675448, MSCA RISE-734749], Swedish Research Council (VR) Swedish Research Council [2019-3684], Vinnova Seal-of-Excellence programVinnova [2019-02205], Ecole Doctorale 3M, university of Rennes 1, Region BretagneRegion Bretagne, Fondation ARC pour la recherche sur le cancerFondation ARC pour la Recherche sur le Cancer [PDF20191209830], Vinnova Seal-of-Excellence program Vinnova [2019-02205], Region Bretagne Region Bretagne, Fondation ARC pour la recherche sur le cancer Fondation ARC pour la Recherche sur le Cancer [PDF20191209830], European Project: 675448,H2020,H2020-MSCA-ITN-2015,TRAIN-ERS(2015), European Project: 777657,H2020-EU.1.3.3. - Stimulating innovation by means of cross-fertilisation of knowledge,777657,MSCA-RISE(2018), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and CRLCC Eugène Marquis (CRLCC)
Subjects: Protein Folding, RNase P, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, IRE1, Protein Serine-Threonine Kinases, Endoplasmic Reticulum, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Endoribonucleases, Animals, Homeostasis, Humans, [CHIM]Chemical Sciences, Enzyme Inhibitors, Mode of action, Molecular Biology, 030304 developmental biology, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Kinase, Chemistry, Endoplasmic reticulum, structure activity relationship (SAR), Cell Biology, unfolded protein response, Endoplasmic Reticulum Stress, Transmembrane protein, Cell biology, Cytosol, structure-based drug design (SBDD), 030220 oncology & carcinogenesis, Unfolded protein response, Protein folding, ER stress, Signal Transduction
Abstract: International audience; The Unfolded Protein response is an adaptive pathway triggered upon alteration of endoplasmic reticulum (ER) homeostasis. It is transduced by three major ER stress sensors, among which the Inositol Requiring Enzyme 1 (IRE1) is the most evolutionarily conserved. IRE1 is an ER-resident type I transmembrane protein exhibiting an ER luminal domain that senses the protein folding status and a catalytic kinase and RNase cytosolic domain. In recent years, IRE1 has emerged as a relevant therapeutic target in various diseases including degenerative, inflammatory and metabolic pathologies and cancer. As such several drugs altering IRE1 activity were developed that target either catalytic activity and showed some efficacy in preclinical pathological mouse models. In this review, we describe the different drugs identified to target IRE1 activity as well as their mode of action from a structural perspective, thereby identifying common and different modes of action. Based on this information we discuss on how new IRE1-targeting drugs could be developed that outperform the currently available molecules.
Published: 2021
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10. Soluble CD95L in cancers and chronic inflammatory disorders, a new therapeutic target?

Author: Patrick Blanco, Patrick Legembre, Keerthi Kurma, Andrea Boizard-Moracchini, Mickael Jean, Pierre Vacher, Gaël Galli, Jonchère, Laurent, Impact du CD95L, dans la dysfonction des lymphocytes T exprimant l'IL-17 au cours du lupus - - FASILE2017 - ANR-17-CE15-0027 - AAPG2017 - VALID, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by INCa PLBIO (PLBIO 2018-132), Ligue Contre le Cancer, Fondation ARC, Fondation de France (Price Jean Valade), and ANR PRCE (ANR-17-CE15-0027)., ANR-17-CE15-0027,FASILE,Impact du CD95L, dans la dysfonction des lymphocytes T exprimant l'IL-17 au cours du lupus(2017), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-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)-Université de Bordeaux (UB), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)
Subjects: Cancer Research, Fas Ligand Protein, [SDV.CAN]Life Sciences [q-bio]/Cancer, Fas ligand, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, [CHIM] Chemical Sciences, Genetics, Medicine, [CHIM]Chemical Sciences, Humans, 030304 developmental biology, Inflammation, 0303 health sciences, Metalloproteinase, business.industry, Ligand (biochemistry), Pathophysiology, Transmembrane protein, 3. Good health, Oncology, Apoptosis, 030220 oncology & carcinogenesis, Chronic Disease, Cancer research, Tumor necrosis factor alpha, Signal transduction, business
Abstract: International audience; Although CD95L (also known as FasL) is still predominantly considered as a death ligand that induces apoptosis in infected and transformed cells, substantial evidence indicate that it can also trigger non-apoptotic signaling pathways whose pathophysiological roles remain to be fully elucidated. The transmembrane ligand CD95L belongs to the tumor necrosis factor (TNF) superfamily. After cleavage by metalloprotease, its soluble form (s-CD95L) fails to trigger the apoptotic program but instead induces signaling pathways promoting the aggressiveness of certain inflammatory disorders such as autoimmune diseases and cancers. We propose to evaluate the various pathologies in which the metalloprotease-cleaved CD95L is accumulated and analyze whether this soluble ligand may play a significant role in the pathology progression. Based on the TNFα-targeting therapeutics, we envision that targeting the soluble form of CD95L may represent a very attractive therapeutic option in the pathologies depicted herein.
Published: 2021
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11. Death sentence: The tale of a fallen endoplasmic reticulum

Author: Eric Chevet, Elodie Lafont, Eoghan P. McGrath, Federica G. Centonze, Tony Avril, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), This work was funded by grants from Institut National du Cancer (INCa PLBIO), Fondation pour la Recherche Médicale (FRM, équipe labellisée 2018), Agence Nationale de la Recherche (eRARE, eranet) to EC, and la Ligue Contre le Cancer (comités 35, 56 & 85 -AAP2019) to TA. EMG was funded by an Institut de Neurosciences Cliniques de Rennes (INCR) award. EL was supported by funds from the Fondation ARC and Fondation de France., Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent
Subjects: 0301 basic medicine, Cell death, Programmed cell death, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Unfolded protein response, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Autophagy, Pyroptosis, Animals, Humans, Ferroptosis, Molecular Biology, Mechanism (biology), Endoplasmic reticulum, Cell Biology, Endoplasmic Reticulum Stress, Cell biology, 030104 developmental biology, Gene Expression Regulation, 030220 oncology & carcinogenesis, Protein folding
Abstract: International audience; Endoplasmic Reticulum (ER) stress signaling is an adaptive mechanism triggered when protein folding demand overcomes the folding capacity of this compartment, thereby leading to the accumulation of improperly folded proteins. This stress signaling pathway is named the Unfolded Protein Response (UPR) and aims at restoring ER homeostasis. However, if this fails, mechanisms orienting cells towards death processes are initiated. Herein, we summarize the most recent findings connecting ER stress and the UPR with identified death mechanisms including apoptosis, necrosis, pyroptosis, ferroptosis, and autophagy. We highlight new avenues that could be investigated and controlled through actionable mechanisms in physiology and pathology.
Published: 2021
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12. CXCR6 deficiency impairs cancer vaccine efficacy and CD8+ resident memory T-cell recruitment in head and neck and lung tumors

Author: Karaki, Soumaya, Blanc, Charlotte, Tran, Thi, Galy-Fauroux, Isabelle, Mougel, Alice, Dransart, Estelle, Anson, Marie, Tanchot, Corinne, Paolini, Lea, Gruel, Nadege, Gibault, Laure, Lepimpec-Barhes, Francoise, Fabre, Elizabeth, Benhamouda, Nadine, Badoual, Cecile, Damotte, Diane, Donnadieu, Emmanuel, Kobold, Sebastian, Mami-Chouaib, Fathia, Golub, Rachel, Johannes, Ludger, Tartour, Eric, Vougny, Marie-Christine, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, 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), Equipe labellisée Ligue contre le Cancer, 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), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Recherche Translationnelle, Institut Curie [Paris], Service d’anatomo‑pathologie [AP-HP Hôpital Européen Georges Pompidou] (Centre de Ressources biologiques), 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), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), 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), Center for Integrated Protein Science (CIPSM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU)-Helmholtz Zentrum München = German Research Center for Environmental Health, German Center for Lung Research - DZL [Munich, Germany], Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), This work has been funded by Fondation ARC, INCA PLBio, Labex Immuno-Oncology, Site intégré de recherche en cancérologie (SIRIC CARPEM, SIRIC Curie), Cancéropole d’Ile de France, Carnot Curie Cancer, FONCER. SK is supported by the European Research Council (grant 756017, ARMOR-T)., ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), 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]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), Département de recherche translationnelle, 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-Ludwig Maximilian University of Munich [Germany] (LMU München), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), École Pratique des Hautes Études (EPHE), and Technical University of Munich (TUM)-Ludwig Maximilian University of Munich [Germany] (LMU München)-Helmholtz-Zentrum München (HZM)
Subjects: Lung Neoplasms, [SDV.IMM] Life Sciences [q-bio]/Immunology, Vaccine Efficacy, immunization, Cancer Vaccines, Memory T Cells, Lymphocytes, Tumor-Infiltrating, Cell Line, Tumor, Tumor Microenvironment, Animals, Humans, Administration, Intranasal, RC254-282, Receptors, CXCR6, Mice, Knockout, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Basic Tumor Immunology, Chemokine CXCL16, adaptive immunity, vaccination, Tumor Burden, Mice, Inbred C57BL, Phenotype, Head and Neck Neoplasms, CD8-positive T-lymphocytes, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Immunologic Memory
Abstract: International audience; Background Resident memory T lymphocytes (TRM) are located in tissues and play an important role in immunosurveillance against tumors. The presence of TRM prior to treatment or their induction is associated to the response to anti-Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1) immunotherapy and the efficacy of cancer vaccines. Previous work by our group and others has shown that the intranasal route of vaccination allows more efficient induction of these cells in head and neck and lung mucosa, resulting in better tumor protection. The mechanisms of in vivo migration of these cells remains largely unknown, apart from the fact that they express the chemokine receptor CXCR6.Methods We used CXCR6-deficient mice and an intranasal tumor vaccination model targeting the Human Papillomavirus (HPV) E7 protein expressed by the TC-1 lung cancer epithelial cell line. The role of CXCR6 and its ligand, CXCL16, was analyzed using multiparametric cytometric techniques and Luminex assays.Human biopsies obtained from patients with lung cancer were also included in this study.Results We showed that CXCR6 was preferentially expressed by CD8+ TRM after vaccination in mice and also on intratumoral CD8+ TRM derived from human lung cancer. We also demonstrate that vaccination of Cxcr6-deficient mice induces a defect in the lung recruitment of antigen-specific CD8+ T cells, preferentially in the TRM subsets. In addition, we found that intranasal vaccination with a cancer vaccine is less effective in these Cxcr6-deficient mice compared with wild-type mice, and this loss of efficacy is associated with decreased recruitment of local antitumor CD8+ TRM. Interestingly, intranasal, but not intramuscular vaccination induced higher and more sustained concentrations of CXCL16, compared with other chemokines, in the bronchoalveolar lavage fluid and pulmonary parenchyma.Conclusions This work demonstrates the in vivo role of CXCR6-CXCL16 axis in the migration of CD8+ resident memory T cells in lung mucosa after vaccination, resulting in the control of tumor growth. This work reinforces and explains why the intranasal route of vaccination is the most appropriate strategy for inducing these cells in the head and neck and pulmonary mucosa, which remains a major objective to overcome resistance to anti-PD-1/PD-L1, especially in cold tumors.
Published: 2021
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13. Secretion, Maturation, and Activity of a Quorum Sensing Peptide (GSP) Inducing Bacteriocin Transcription in Streptococcus gallolyticus

Author: Ryan W. Mull, Anthony Harrington, Shaynoor Dramsi, Yftah Tal-Gan, Laurence du Merle, Alexis Proutière, University of Nevada [Reno], Biologie des Bactéries pathogènes à Gram-positif - Biology of Gram-Positive Pathogens, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work was supported in part (Tal-Gan lab) by a grant from the National Science Foundation (CHE-1808370) and in part by the Institut National contre le Cancer (INCA) PLBIO 16-025 (to S. Dramsi)., We thank C. R. Bikash (University of Nevada, Reno) for providing purified S. mutans 21-mer CSP and D. G. Cvitkovitch (University of Toronto) for generously providing S. mutans SMCOM2 (ΔcomC pcomX::lacZ)., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Signal Transduction, Bodily Secretions, [SDV]Life Sciences [q-bio], ATP-binding cassette transporter, medicine.disease_cause, MESH: Quorum Sensing, Pheromones, MESH: Membrane Transport Proteins, MESH: Bodily Secretions, MESH: Bacteriocins, MESH: Bacterial Proteins, MESH: Pheromones, MESH: Gene Expression Regulation, Bacterial, 0303 health sciences, biology, MESH: Peptides, Streptococcus, quorum sensing, peptide, QR1-502, 3. Good health, MESH: ATP-Binding Cassette Transporters, Signal Transduction, Research Article, Streptococcus gallolyticus, MESH: Peptide Hydrolases, Microbiology, bacteriocins, Host-Microbe Biology, 03 medical and health sciences, Bacterial Proteins, Bacteriocin, Virology, medicine, MESH: Streptococcus gallolyticus, Gene, 030304 developmental biology, 030306 microbiology, MESH: Transcriptome, Lactococcus lactis, Membrane Transport Proteins, Gene Expression Regulation, Bacterial, biology.organism_classification, Quorum sensing, ATP-Binding Cassette Transporters, Heterologous expression, Peptides, Transcriptome, Peptide Hydrolases
Abstract: International audience; Streptococcus gallolyticus subsp. gallolyticus is an emerging opportunistic pathogen responsible for septicemia and endocarditis in the elderly. Invasive infections by S. gallolyticus subsp. gallolyticus are strongly linked to the occurrence of colorectal cancer (CRC). It was previously shown that increased secondary bile salts under CRC conditions enhance the bactericidal activity of gallocin, a bacteriocin produced by S. gallolyticus subsp. gallolyticus, enabling it to colonize the mouse colon by outcompeting resident enterococci (L. Aymeric, F. Donnadieu, C. Mulet, L. du Merle, et al., Proc Natl Acad Sci U S A 115:E283-E291, 2018, https://doi.org/10.1073/pnas.1715112115). In a separate study, we showed that S. gallolyticus subsp. gallolyticus produces and secretes a 21-mer peptide that activates bacteriocin production (A. Proutière, L. du Merle, B. Périchon, H. Varet, et al., mBio 11:e03187-20, 2020, https://doi.org/10.1128/mBio.03187-20). This peptide was named CSP because of its sequence similarity with competence-stimulating peptides found in other streptococci. Here, we demonstrate that CSP is a bona fide quorum sensing peptide involved in activation of gallocin gene transcription. We therefore refer to CSP as GSP (gallocin-stimulating peptide). GSP displays some unique features, since its N-terminal amino acid lies three residues after the double glycine leader sequence. Here, we set out to investigate the processing and export pathway that leads to mature GSP. Heterologous expression in Lactococcus lactis of the genes encoding GSP and the BlpAB transporter is sufficient to produce the 21-mer form of GSP in the supernatant, indicating that S. gallolyticus subsp. gallolyticus BlpAB displays an atypical cleavage site. We also conducted the first comprehensive structure-activity relationship (SAR) analysis of S. gallolyticus subsp. gallolyticus GSP to identify its key structural features and found that unlike many other similar streptococci signaling peptides (such as CSPs), nearly half of the mature GSP sequence can be removed (residues 1 to 9) without significantly impacting the peptide activity.IMPORTANCE Streptococcus gallolyticus subsp. gallolyticus is an opportunistic pathogen associated with colorectal cancer (CRC) and endocarditis. S. gallolyticus subsp. gallolyticus utilizes quorum sensing (QS) to regulate the production of a bacteriocin (gallocin) and gain a selective advantage in colonizing the colon. In this article, we report (i) the first structure-activity relationship study of the S. gallolyticus subsp. gallolyticus QS pheromone that regulates gallocin production, (ii) evidence that the active QS pheromone is processed to its mature form by a unique ABC transporter and not processed by an extracellular protease, and (iii) supporting evidence of interspecies interactions between streptococcal pheromones. Our results revealed the minimal pheromone scaffold needed for gallocin activation and uncovered unique interactions between two streptococcal QS signals that warrant further stu
Published: 2021
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14. Characterization of a Four-Component Regulatory System Controlling Bacteriocin Production in Streptococcus gallolyticus

Author: Shaynoor Dramsi, Laurence du Merle, Patrick Trieu-Cuot, Bruno Périchon, Myriam Gominet, Hugo Varet, Alexis Proutière, Biologie des Bactéries pathogènes à Gram-positif - Biology of Gram-Positive Pathogens, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Pôle Biomics (C2RT), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris]-Institut Pasteur [Paris], This study was funded by the Institut National contre le Cancer (INCA) PLBIO 16-025 to S. Dramsi and from the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (grant no. ANR-10-LABX-62-IBEID)., We particularly thank Odile Sismeiro for the construction of the transcriptome library and Rachel Legendre for the bioinformatic analysis of the transcriptome and its deposition to the GEO database. We are also grateful to Christophe Rusniok for his help in the search of LytTR-only proteins, Christine Dang for the reporter plasmid construction, and Tarek Msadek for careful and critical reading of the manuscript. We also thank Maria Vittoria Mazzuoli for providing her expertise in EMSAs and Gaël Millot for his help with the statistical analysis of qRT-PCR data., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)-Institut Pasteur [Paris] (IP)
Subjects: Histidine Kinase, Streptococcus gallolyticus, [SDV]Life Sciences [q-bio], Biology, Microbiology, bacteriocins, Host-Microbe Biology, Conserved sequence, 03 medical and health sciences, Bacterial Proteins, Bacteriocin, Streptococcal Infections, Virology, Gene, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, 030306 microbiology, Gene Expression Profiling, Histidine kinase, Quorum Sensing, Streptococcus, Gene Expression Regulation, Bacterial, QR1-502, Gastrointestinal Microbiome, 3. Good health, DNA-Binding Proteins, Response regulator, Quorum sensing, Genes, Bacterial, regulation of gene expression, Transcriptome, Genome, Bacterial, Research Article
Abstract: Bacteriocins are natural antimicrobial peptides produced by bacteria to kill closely related competitors. The opportunistic pathogen Streptococcus gallolyticus subsp. gallolyticus was recently shown to outcompete commensal enterococci of the murine microbiota under tumoral conditions thanks to the production of a two-peptide bacteriocin named gallocin. Here, we identified four genes involved in the regulatory control of gallocin in S. gallolyticus subsp. gallolyticus UCN34 that encode a histidine kinase/response regulator two-component system (BlpH/BlpR), a secreted peptide (GSP [gallocin-stimulating peptide]), and a putative regulator of unknown function (BlpS). While BlpR is a typical 243-amino-acid (aa) response regulator possessing a phospho-receiver domain and a LytTR DNA-binding domain, BlpS is a 108-aa protein containing only a LytTR domain. Our results showed that the secreted peptide GSP activates the dedicated two-component system BlpH/BlpR to induce gallocin transcription. A genome-wide transcriptome analysis indicates that this regulatory system (GSP-BlpH/BlpR) is specific for bacteriocin production. Importantly, as opposed to BlpR, BlpS was shown to repress gallocin gene transcription. A conserved operator DNA sequence of 30 bp was found in all promoter regions regulated by BlpR and BlpS. Electrophoretic mobility shift assays (EMSA) and footprint assays showed direct and specific binding of BlpS and BlpR to various regulated promoter regions in a dose-dependent manner on this conserved sequence. Gallocin expression appears to be tightly controlled in S. gallolyticus subsp. gallolyticus by quorum sensing and antagonistic activity of 2 LytTR-containing proteins. Competition experiments in gut microbiota medium and 5% CO2 to mimic intestinal conditions demonstrate that gallocin is functional under these in vivo-like conditions. IMPORTANCEStreptococcus gallolyticus subsp. gallolyticus, formerly known as Streptococcus bovis biotype I, is an opportunistic pathogen causing septicemia and endocarditis in the elderly often associated with asymptomatic colonic neoplasia. Recent studies indicate that S. gallolyticus subsp. gallolyticus is both a driver and a passenger of colorectal cancer. We previously showed that S. gallolyticus subsp. gallolyticus produces a bacteriocin, termed gallocin, enabling colonization of the colon under tumoral conditions by outcompeting commensal members of the murine microbiota such as Enterococcus faecalis. Here, we identified and extensively characterized a four-component system that regulates gallocin production. Gallocin gene transcription is activated by a secreted peptide pheromone (GSP) and a two-component signal transduction system composed of a transmembrane histidine kinase receptor (BlpH) and a cytosolic response regulator (BlpR). Finally, a DNA-binding protein (BlpS) was found to repress gallocin genes transcription, likely by antagonizing BlpR. Understanding gallocin regulation is crucial to prevent S. gallolyticus subsp. gallolyticus colon colonization under tumoral conditions.
Published: 2021
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15. Identification of common predisposing loci to hematopoietic cancers in four dog breeds

Author: Jérôme Abadie, Pascale Quignon, Maud Rimbault, Thomas Derrien, Nadine Botherel, Patrick Devauchelle, Caroline Dufaure de Citres, Edouard Cadieu, Catherine André, Benoit Hedan, Amaury Vaysse, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Antagene France, MICEN-Vet, Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), INCa PLBio [2012-103], Aviesan [MTS 2012-06], American Kennel Club Canine Health fundation [2446], ANRFrench National Research Agency (ANR) [ANR-11INBS-0003], ANR-11-INBS-0003,CRB-Anim,Réseau de Centres de Ressources Biologiques pour les animaux domestiques(2011), 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 ), and École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)
Subjects: Cancer Research, Heredity, Lymphoma, Epidemiology, Genome-wide association study, Histiocytic sarcoma, QH426-470, Hematologic Cancers and Related Disorders, 0302 clinical medicine, CDKN2A, Medicine and Health Sciences, Dog Diseases, Genetics (clinical), Genetics, Mammals, 0303 health sciences, Pets and Companion Animals, Cancer Risk Factors, Eukaryota, Chromosome Mapping, High-Throughput Nucleotide Sequencing, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Genomics, Hematology, 3. Good health, Genetic Mapping, Oncology, 030220 oncology & carcinogenesis, Hematologic Neoplasms, Vertebrates, Research Article, Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Dogs, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Genome-Wide Association Studies, Animals, Humans, Genetic Predisposition to Disease, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Cyclin-Dependent Kinase Inhibitor p16, 030304 developmental biology, Genetic association, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Haplotype, Organisms, Cancer, Biology and Life Sciences, Computational Biology, Cancers and Neoplasms, Human Genetics, medicine.disease, Genome Analysis, Haplotypes, Genetic Loci, Medical Risk Factors, Amniotes, Histiocytic Sarcoma, Zoology, Imputation (genetics), Genome-Wide Association Study
Abstract: Histiocytic sarcoma (HS) is a rare but aggressive cancer in both humans and dogs. The spontaneous canine model, which has clinical, epidemiological, and histological similarities with human HS and specific breed predispositions, provides a unique opportunity to unravel the genetic basis of this cancer. In this study, we aimed to identify germline risk factors associated with the development of HS in canine-predisposed breeds. We used a methodology that combined several genome-wide association studies in a multi-breed and multi-cancer approach as well as targeted next-generation sequencing, and imputation We combined several dog breeds (Bernese mountain dogs, Rottweilers, flat-coated retrievers, and golden retrievers), and three hematopoietic cancers (HS, lymphoma, and mast cell tumor). Results showed that we not only refined the previously identified HS risk CDKN2A locus, but also identified new loci on canine chromosomes 2, 5, 14, and 20. Capture and targeted sequencing of specific loci suggested the existence of regulatory variants in non-coding regions and methylation mechanisms linked to risk haplotypes, which lead to strong cancer predisposition in specific dog breeds. We also showed that these canine cancer predisposing loci appeared to be due to the additive effect of several risk haplotypes involved in other hematopoietic cancers such as lymphoma or mast cell tumors as well. This illustrates the pleiotropic nature of these canine cancer loci as observed in human oncology, thereby reinforcing the interest of predisposed dog breeds to study cancer initiation and progression., Author summary Because of specific breed structures and artificial selection, pet dogs suffer from numerous genetic diseases, including cancers and represent a unique spontaneous model of human cancers. Here, we focused on histiocytic sarcoma (HS), a rare and highly aggressive cancer in humans. In this study, we have used spontaneous affected and unaffected dogs from three predisposed dog breeds to identify loci involved in HS predisposition. Through genetic analyses, we showed that these canine cancer predispositions are due to the additive effect of several risk haplotypes also involved in the predisposition of other hematopoietic cancers. The corresponding chromosomal regions in humans are involved in the predisposition of several cancers and are also associated with immune traits. This study demonstrates the pleiotropic nature of these canine cancer loci as observed in human oncology, thereby reinforcing the interest of predisposed dog breeds to study mechanisms involved in cancer initiation.
Published: 2021
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16. Integration of Raman spectra with transcriptome data in glioblastoma multiforme defines tumour subtypes and predicts patient outcome

Author: Mari McMahon, Luis Cano, Aristotelis Chatziioannou, Marc Aubry, Alain Fautrel, Amandine Etcheverry, Eleftherios Pilalis, Eric Chevet, Pierre-Jean Le Reste, CHU Pontchaillou [Rennes], Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Rennes Brain Cancer Team (REACT), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), CRLCC Eugène Marquis (CRLCC), Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National du Cancer (INCa PLBIO) Institut National du Cancer (INCA) France, Fondation pour la Recherche Medicale (FRM) Fondation pour la Recherche Medicale [DEQ20180339169], EU H2020 MSCA [ITN-675448], MSCA [RISE-734749], Irish Research Council Irish Research Council for Science, Engineering and Technology, ARED International PhD fellowship from \'Region Bretagne\', INSERM International Research Project (TUPRIC), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Jonchère, Laurent
Subjects: Adult, Male, Cell type, Disease outcome, [SDV]Life Sciences [q-bio], Computational biology, Spectrum Analysis, Raman, Transcriptome, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, medicine, Humans, data integration, 030304 developmental biology, Aged, 0303 health sciences, Chemistry, Brain Neoplasms, glioblastoma, Cell Biology, Original Articles, Middle Aged, medicine.disease, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Raman spectroscopy, symbols, Molecular Medicine, Female, Original Article, Imaging technique, Glioblastoma
Abstract: International audience; Raman spectroscopy is an imaging technique that has been applied to assess molecular compositions of living cells to characterize cell types and states. However, owing to the diverse molecular species in cells and challenges of assigning peaks to specific molecules, it has not been clear how to interpret cellular Raman spectra. Here, we provide firm evidence that cellular Raman spectra (RS) and transcriptomic profiles of glioblastoma can be computationally connected and thus interpreted. We find that the dimensions of high-dimensional RS and transcriptomes can be reduced and connected linearly through a shared low-dimensional subspace. Accordingly, we were able to predict global gene expression profiles by applying the calculated transformation matrix to Raman spectra and vice versa. From these analyses, we extract a minimal gene expression signature associated with specific RS profiles and predictive of disease outcome.
Published: 2021
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17. Maintenance of Endoplasmic Reticulum Protein Homeostasis in Cancer: Friend or Foe

Author: Eric Chevet, Mari McMahon, Afshin Samali, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), National University of Ireland [Galway] (NUI Galway), Centre Eugène Marquis (CRLCC), This work was funded by grants from the French National Cancer Institute (INCa, PLBIO), the Fondation pour la recherche Médicale (FRM, équipe labellisée 2018) to EC and EU H2020 MSCA ITN-675448 (TRAINERS) and MSCA RISE-734749 (INSPIRED) grants to AS and EC. MMM was funded by scholarships from the Irish Research Council and the 'Région Bretagne' (ARED international PhD) and by a travel grant from the French embassy in Dublin, Ireland., European Project: 675448,H2020,H2020-MSCA-ITN-2015,TRAIN-ERS(2015), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, proteostasis, Endoplasmic reticulum, Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease, 3. Good health, Cell biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Proteostasis, 030220 oncology & carcinogenesis, Protein biosynthesis, medicine, cancer, Protein folding, quality control, Protein quality, Homeostasis, Secretory pathway
Abstract: International audience; The endoplasmic reticulum, as the site of synthesis for proteins in the secretory pathway has evolved select machineries to ensure the correct folding and modification of proteins. However, sometimes these quality control mechanisms fail and proteins are misfolded. Other factors, such as nutrient deprivation, hypoxia or an increased demand on protein synthesis can also cause the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum. There are mechanisms that recognise and deal with this accumulation of protein through degradation and/or export. Many diseases are associated with aberrant quality control mechanisms, and among these, cancer has emerged as a group of diseases that rely on endoplasmic reticulum homeostasis to sustain development and growth. The knowledge of how protein quality control operates in cancer has identified opportunities for these pathways to be pharmacologically targeted, which could lead to newer or more effective treatments in the future.
Published: 2021
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18. IRE1-mediated miRNA maturation in macrophage phosphoinositide signaling

Author: Eric Chevet, Tony Avril, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Institut National du Cancer (INCa PLBIO) Institut National du Cancer (INCA) France, Agence Nationale de la Recherche (ANR) French National Research Agency (ANR), Fondation pour la Recherche Medicale (FRM, equipe labellisee 2018), la Ligue Contre le Cancer (comites 35) [56 85-AAP2019], Agence Nationale de la Recherche (IRE1inNASH)French National Research Agency (ANR), Agence Nationale de la Recherche (eRANET eRARE-ERAAT) French National Research Agency (ANR), ANR-18-CE14-0022,IRE1inNASH,Cibler la voie IRE1 dans la stéatohépatite(2018), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Jonchère, Laurent, and APPEL À PROJETS GÉNÉRIQUE 2018 - Cibler la voie IRE1 dans la stéatohépatite - - IRE1inNASH2018 - ANR-18-CE14-0022 - AAPG2018 - VALID
Subjects: RNase P, Endoribonuclease, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Protein Serine-Threonine Kinases, Phosphatidylinositols, Biochemistry, 03 medical and health sciences, Endonuclease, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Endoribonucleases, microRNA, Genetics, medicine, Humans, News & Views, Molecular Biology, 030304 developmental biology, 0303 health sciences, biology, Macrophages, Endoplasmic reticulum, Endoplasmic Reticulum Stress, Cell biology, Unfolded Protein Response, biology.protein, Unfolded protein response, medicine.symptom, Inositol, 030217 neurology & neurosurgery, Dicer
Abstract: The ER-bound kinase/endoribonuclease (RNase), inositol-requiring enzyme-1 (IRE1), regulates the phylogenetically most conserved arm of the unfolded protein response (UPR). However, the complex biology and pathology regulated by mammalian IRE1 cannot be fully explained by IRE1's one known, specific RNA target, X box-binding protein-1 (XBP1) or the RNA substrates of IRE1-dependent RNA degradation (RIDD) activity. Investigating other specific substrates of IRE1 kinase and RNase activities may illuminate how it performs these diverse functions in mammalian cells. We report that macrophage IRE1 plays an unprecedented role in regulating phosphatidylinositide-derived signaling lipid metabolites and has profound impact on the downstream signaling mediated by the mammalian target of rapamycin (mTOR). This cross-talk between UPR and mTOR pathways occurs through the unconventional maturation of microRNA (miR) 2137 by IRE1's RNase activity. Furthermore, phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P
Published: 2020
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19. When Endoplasmic Reticulum Proteostasis Meets the DNA Damage Response

Author: Alice Blondel, Matías González-Quiroz, Rémy Pedeux, Alfredo Sagredo, Eric Chevet, Claudio Hetz, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidad de Chile = University of Chile [Santiago] (UCHILE), CRLCC Eugène Marquis (CRLCC), Institute of Catalysis and Petroleum Chemistry, Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) fellowship (PCHA/Doctorado Nacional/2016-21160232), Chile, (to M.G-Q.), doctoral fellowship from the Association pour les Recommendations en Dermatologie (ARED)/INSERM Région Bretagne, France, (to A.B.), the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) 3190738 and Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias (FONDAP) GERO-15150012, Chile, (to A.S.), FONDAP program Nº 15150012, Millennium Institute P09-015-F, Fondo de Fomento al Desarrollo Científico y Tecnológico (FONDEF) ID16I10223 and D11E1007, and FONDECYT-T1180186 and Ecos-CONICYT C17S02, Chile, (to C.H.), the Institut National du Cancer (INCa PLBIO), Agence Nationale de la Recherche (ANR) in the framework of European Research Area Network ERAAT, and EU Horizon 2020 Marie Skłodowska-Curie Action (MSCA) ITN-675448 (TRAINERS) and MSCA RISE-734749 (INSPIRED), France, (to E.C.), and the Fondation pour la Recherche Médicale (FMR, DEQ20180339169), Ligue Contre le Cancer Grand Ouest, and INSERM, France, (to R.P.)., European Project: 675448,H2020,H2020-MSCA-ITN-2015,TRAIN-ERS(2015), and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: PERK, DNA damage, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Endoplasmic Reticulum, DNA damage response, Models, Biological, Genomic Instability, 03 medical and health sciences, 0302 clinical medicine, Animals, Humans, 030304 developmental biology, 0303 health sciences, proteostasis, Endoplasmic reticulum, Cell Biology, IRE1α, unfolded protein response, 3. Good health, Cell biology, body regions, Crosstalk (biology), Proteostasis, Apoptosis, ATM, Proteome, biological sciences, Unfolded protein response, Signal transduction, 030217 neurology & neurosurgery, DNA Damage, Signal Transduction
Abstract: International audience; Sustaining both proteome and genome integrity (GI) requires the integration of a wide range of mechanisms and signaling pathways. These comprise, in particular, the unfolded protein response (UPR) and the DNA damage response (DDR). These adaptive mechanisms take place respectively in the endoplasmic reticulum (ER) and in the nucleus. UPR and DDR alterations are associated with aging and with pathologies such as degenerative diseases, metabolic and inflammatory disorders, and cancer. We discuss the emerging signaling crosstalk between UPR stress sensors and the DDR, as well as their involvement in cancer biology.
Published: 2020
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20. PTPN11 mutations in canine and human disseminated histiocytic sarcoma

Author: Jean-Yves Blay, Julia Alten, Jean Donadieu, Matthew Breen, Thomas Derrien, Aurore Coulomb-L'Hermine, Jérôme Abadie, Mélanie Rault, Marie Parrens, Emmanuelle Lechapt Zalcman, Gandhi Damaj, Karima Mokhtari, Gunnar Cario, François Le Loarer, Edouard Cadieu, Nadine Botherel, Christiane Copie-Bergman, Patrick Devauchelle, Benoit Hedan, David Gilot, Christophe Hitte, Catherine André, Ronan Ulvé, Laura Bachelot, 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 ), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), MICEN-Vet, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, GHU Paris Psychiatrie et Neurosciences, Laboratoire d'Hématologie Biologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut du Cerveau = Paris Brain Institute (ICM), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC), Agence Nationale de la Recherche. Grant Number: ANR‐11‐INBS‐0003, American Kennel Club Canine Health Foundation. Grant Numbers: 1557, 2446, 2667, INCa PLBio. Grant Number: 2012‐103, ANR-11-INBS-0003,CRB-Anim,Réseau de Centres de Ressources Biologiques pour les animaux domestiques(2011), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Jonchère, Laurent, Infrastructures - Réseau de Centres de Ressources Biologiques pour les animaux domestiques - - CRB-Anim2011 - ANR-11-INBS-0003 - INBS - VALID, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, MAPK/ERK pathway, Cancer Research, Biopsy, DNA Mutational Analysis, Protein Tyrosine Phosphatase, Non-Receptor Type 11, [SDV.GEN] Life Sciences [q-bio]/Genetics, Histiocytic sarcoma, PTPN11, medicine.disease_cause, Mutually exclusive events, 0302 clinical medicine, Dog Diseases, Child, Aged, 80 and over, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Middle Aged, 3. Good health, spontaneous model, Oncology, Child, Preschool, 030220 oncology & carcinogenesis, dog, Female, KRAS, Mitogen-Activated Protein Kinases, Adult, MAP Kinase Signaling System, [SDV.CAN]Life Sciences [q-bio]/Cancer, histiocytic sarcoma, Young Adult, 03 medical and health sciences, Dogs, Ribonucleases, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, Animals, Humans, Protein Kinase Inhibitors, Histiocyte, Aged, Cell Proliferation, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Tumor Suppressor Proteins, Infant, Aggressive cancer, Histiocytes, medicine.disease, Disease Models, Animal, Cell culture, Mutation, Cancer research, Drug Screening Assays, Antitumor, business
Abstract: International audience; In humans, histiocytic sarcoma (HS) is an aggressive cancer involving histiocytes. Its rarity and heterogeneity explain that treatment remains a challenge. Sharing high clinical and histopathological similarities with human HS, the canine HS is conversely frequent in specific breeds and thus constitutes a unique spontaneous model for human HS to decipher the genetic bases and to explore therapeutic options. We identified sequence alterations in the MAPK pathway in at least 63.9% (71/111) of HS cases with mutually exclusive BRAF (0.9%; 1/111), KRAS (7.2%; 8/111) and PTPN11 (56.75%; 63/111) mutations concentrated at hotspots common to human cancers. Recurrent PTPN11 mutations are associated to visceral disseminated HS subtype in dogs, the most aggressive clinical presentation. We then identified PTPN11 mutations in 3/19 (15.7%) human HS patients. Thus, we propose PTPN11 mutations as key events for a specific subset of human and canine HS the visceral disseminated form. Finally, by testing drugs targeting the MAPK pathway in eight canine HS cell lines, we identified a better anti-proliferation activity of MEK inhibitors than PTPN11 inhibitors in canine HS neoplastic cells. In combination, these results illustrate the relevance of naturally affected dogs in deciphering genetic mechanisms and selecting efficient targeted therapies for such rare and aggressive cancers in humans.
Published: 2020
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21. Robust and Scalable Learning of Complex Intrinsic Dataset Geometry via ElPiGraph

Author: Evgeny M. Mirkes, Louis Faure, Jonathan Bac, Alexis Martin, Luca Albergante, Huidong Chen, Luca Pinello, Andrei Zinovyev, Emmanuel Barillot, Alexander N. Gorban, Institut Curie [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - 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), Centre de Bioinformatique (CBIO), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Sensyne Health [Oxford], University of Leicester, Lobachevsky State University [Nizhni Novgorod], Centre de Recherches Interdisciplinaires [Paris] (CRI), Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], ECE Paris – Ecole d'ingénieurs, Medical University of Vienna (MUW), INCa PLBIO program, CALYS, INCA_11692ITMO Cancer SysBio program (MOSAIC)Grant number 2018-182734 from the Chan Zuckerberg Initiative DAF, ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), European Project: 826121,iPaediatricCurie, Mines Paris - PSL (École nationale supérieure des mines de Paris), Zinovyev, Andrei, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, European Union’s Horizon 2020 program (grant No. 826121, iPC project) - iPaediatricCurie - 826121 - INCOMING, and Medizinische Universität Wien = Medical University of Vienna
Subjects: Theoretical computer science, Point cloud, General Physics and Astronomy, lcsh:Astrophysics, topological grammars, Article, principal graphs, 03 medical and health sciences, 0302 clinical medicine, Software, data approximation, lcsh:QB460-466, principal trees, lcsh:Science, Geometry and topology, 030304 developmental biology, Complex data type, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], business.industry, software, Topological graph, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], lcsh:QC1-999, Scalability, Unsupervised learning, Topological graph theory, lcsh:Q, business, lcsh:Physics, 030217 neurology & neurosurgery
Abstract: Multidimensional datapoint clouds representing large datasets are frequentlycharacterized by non‐trivial low‐dimensional geometry and topology which can be recovered byunsupervised machine learning approaches, in particular, by principal graphs. Principal graphsapproximate the multivariate data by a graph injected into the data space with some constraintsimposed on the node mapping. Here we present ElPiGraph, a scalable and robust method forconstructing principal graphs. ElPiGraph exploits and further develops the concept of elasticenergy, the topological graph grammar approach, and a gradient descent‐like optimization of thegraph topology. The method is able to withstand high levels of noise and is capable ofapproximating data point clouds via principal graph ensembles. This strategy can be used toestimate the statistical significance of complex data features and to summarize them into a singleconsensus principal graph. ElPiGraph deals efficiently with large datasets in various fields such asbiology, where it can be used for example with single‐cell transcriptomic or epigenomic datasets toinfer gene expression dynamics and recover differentiation landscapes.
Published: 2020
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22. CD95/Fas and metastatic disease: What does not kill you makes you stronger

Author: Jean Philippe Guégan, Patrick Legembre, Thomas Ducret, Pierre Vacher, Jean-François Quignard, Christophe Ginestier, Emmanuelle Charafe-Jauffret, Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, INCa PLBIO, Ligue Contre le Cancer, Fondation ARC, ANR PRCE, Canceropole GO, Region Bretagne, Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 Bergonié [Bordeaux], and UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, MAPK/ERK pathway, Cytotoxicity, Immunologic, Cancer Research, Fas Ligand Protein, TNF, chemical and pharmacologic phenomena, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Immunomodulation, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, hemic and lymphatic diseases, Homeostasis, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, fas Receptor, Neoplasm Metastasis, Receptor, Migration, Cytoskeleton, Neoplasm Staging, Cell migration, hemic and immune systems, Fas receptor, biological factors, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Neoplastic Stem Cells, Cytokine secretion, Calcium, Signal transduction, biological phenomena, cell phenomena, and immunity, Protein Binding, Signal Transduction
Abstract: International audience; CD95 (also known as Fas) is the prototype of death receptors; however, evidence suggests that this receptor mainly implements non-apoptotic signaling pathways such as NF-κB, MAPK, and PI3K that are involved in cell migration, differentiation, survival, and cytokine secretion. At least two different forms of CD95 L exist. The multi-aggregated transmembrane ligand (m-CD95 L) is cleaved by metalloproteases to release a homotrimeric soluble ligand (s-CD95 L). Unlike m-CD95 L, the interaction between s-CD95 L and its receptor CD95 fails to trigger apoptosis, but instead promotes calcium-dependent cell migration, which contributes to the accumulation of inflammatory Th17 cells in damaged organs of lupus patients and favors cancer cell invasiveness. Novel inhibitors targeting the pro-inflammatory roles of CD95/CD95 L may provide attractive therapeutic options for patients with chronic inflammatory disorders or cancer. This review discusses the roles of the CD95/CD95 L pair in cell migration and metastasis.
Published: 2020
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23. A guide to assessing Endoplasmic Reticulum homeostasis and stress in mammalian systems

Author: Daria Sicari, Aeid Igbaria, Laurent Combettes, Eric Chevet, Agnès Delaunay-Moisan, Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CRLCC Eugène Marquis (CRLCC), Stress Oxydatif et Cancer (SOC), Département Biologie Cellulaire (BioCell), 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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), AcknowledgementsThis work was funded by grants from InstitutNational du Cancer (INCa PLBIO), Fondation pourla Recherche Medicale (FRM,equipe labellisee 2018),ANR (ERAAT), MSCA RISE-734749 (INSPIRED)grants to EC. DS was supported by an AIRC fellow-ship for Abroad., and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Activating transcription factor, ER redox state, ER structure, UPR, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Endoplasmic Reticulum, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Animals, Homeostasis, Humans, Molecular Biology, Secretory pathway, Kinase, Endoplasmic reticulum, Cell Biology, Endoplasmic Reticulum Stress, Transmembrane protein, Cell biology, 030104 developmental biology, Calcium distribution, 030220 oncology & carcinogenesis, Unfolded protein response, Unfolded Protein Response, Signal transduction, ER stress, Signal Transduction
Abstract: International audience; The endoplasmic reticulum (ER) is a multifunctional organelle that constitutes the entry into the secretory pathway. The ER contributes to the maintenance of cellular calcium homeostasis, lipid synthesis and productive secretory, and transmembrane protein folding. Physiological, chemical, and pathological factors that compromise ER homeostasis lead to endoplasmic reticulum stress (ER stress). To cope with this situation, cells activate an adaptive signaling pathway termed the unfolded protein response (UPR) that aims at restoring ER homeostasis. The UPR is transduced through post‐translational, translational, post‐transcriptional, and transcriptional mechanisms initiated by three ER‐resident sensors, inositol‐requiring protein 1α, activating transcription factor 6α, and PRKR‐like endoplasmic reticulum kinase. Determining the in and out of ER homeostasis control and UPR activation still represents a challenge for the community. Hence, standardized criteria and methodologies need to be proposed for monitoring ER homeostasis and ER stress in different model systems. Here, we summarize the pathways that are activated during ER stress and provide approaches aimed at assess ER homeostasis and stress in vitro and in vivo mammalian systems that can be used by researchers to plan and interpret experiments. We recommend the use of multiple assays to verify ER stress because no individual assay is guaranteed to be the most appropriate one.
Published: 2020
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24. Synthesis of peptidomimetics and chemo-biological tools for CD95/PLCγ1 interaction analysis

Author: Nicolas Levoin, Patrick Legembre, Amanda Poissonnier, Pierre van de Weghe, Ha Thanh Nguyen, Daniel Best, Mickael Jean, Pierre Vacher, Jean-Philippe Guégan, Florence Jouan, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe labellisée Ligue contre le Cancer, Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioprojet-Biotech, INCa PLBIO, Ligue Contre le Cancer, Fondation ARC, ANR PRCE, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], and UNICANCER-UNICANCER
Subjects: Peptidomimetic, Clinical Biochemistry, Pharmaceutical Science, Lupus, Biotin, Peptide, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Phospholipase, 01 natural sciences, Biochemistry, Cell Movement, Cell Line, Tumor, Drug Discovery, medicine, Humans, Cell migration, fas Receptor, Receptor, Molecular Biology, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, 010405 organic chemistry, Chemistry, Phospholipase C gamma, Organic Chemistry, Fas, Fas receptor, 3. Good health, 0104 chemical sciences, Cell biology, Molecular Docking Simulation, 010404 medicinal & biomolecular chemistry, Apoptosis, CD95, Molecular Medicine, Th17, Peptidomimetics, medicine.symptom, Protein Multimerization, PPI inhibitor, Protein Binding
Abstract: The death receptor CD95 (also known as Fas) induces apoptosis through protein/protein association and the formation of the death-inducing signaling complex. On the other hand, in certain biological conditions, this receptor recruits different proteins and triggers the formation of another complex designated motility-inducing signaling complex, which promotes cell migration and inflammation. This pathway relies on a short sequence of CD95, called calcium-inducing domain (CID), which interacts with the phospholipase PLCγ1. To better understand how CID/PLCγ1 interaction occurs, we synthesized different α-AA peptides mimicking CID. Some of these peptidomimetics are as potent as the natural peptide to disrupt the CID/PLCγ1 interaction and cell migration, and showed improved pharmacokinetic properties. We also generated biotinyl- and palmitoyl-labelled peptidomimetics, useful chemico-biological tools to further explore the pro-inflammatory signal of CD95, which plays an important role in the pathogenesis of lupus and other autoimmune diseases.
Published: 2019
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25. Serum CD95L Level Correlates with Tumor Immune Infiltration and Is a Positive Prognostic Marker for Advanced High-Grade Serous Ovarian Cancer

Author: Jean Levêque, Julien Corné, Matthieu Le Gallo, Patrick Legembre, Alain Fautrel, Marie Le Boulch, Aurélie Cauchois, Sébastien Henno, Bruno Laviolle, Vincent Lavoué, Estelle Le Pabic, Clotilde Poupon, Thibault De La Motte Rouge, Nathalie Rioux-Leclercq, Véronique Catros, Centre Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CRLCC Eugène Marquis (CRLCC), 2017, Ligue Contre le Cancer, 2016, Fondation ARC pour la Recherche sur le Cancer, 2014, La Vannetaise, PLASTICO 2017, Canceropole Grand Ouest, 2017, INCa PLBIO, 2018, ANR PRCE, Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Cancer Research, Fas Ligand Protein, medicine.medical_treatment, CD3, [SDV]Life Sciences [q-bio], tumor immune infiltration, [SDV.CAN]Life Sciences [q-bio]/Cancer, Apoptosis, T-Lymphocytes, Regulatory, 03 medical and health sciences, 0302 clinical medicine, Immune system, Lymphocytes, Tumor-Infiltrating, Cell Movement, medicine, Biomarkers, Tumor, Cytotoxic T cell, Humans, Molecular Biology, Cell Proliferation, Neoplasm Staging, CD20, Ovarian Neoplasms, B-Lymphocytes, biology, business.industry, FOXP3, Forkhead Transcription Factors, Immunotherapy, soluble CD95 ligand, Middle Aged, Prognosis, High grade serous ovarian cancer, 3. Good health, Cystadenocarcinoma, Serous, Granzyme B, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Female, business, CD8
Abstract: Soluble CD95L (s-CD95L) is a chemoattractant for certain lymphocyte subpopulations. We examined whether this ligand is a prognostic marker for high-grade serous ovarian cancer (HGSOC) and whether it is associated with accumulation of immune cells in the tumor. Serum s-CD95L levels in 51 patients with advanced ovarian cancer were tested by ELISA. IHC staining of CD3, CD4, CD8, CD20, CD163, CD31, FoxP3, CCR6, IL-17, Granzyme B, PD-L1, and membrane CD95L was used to assess tumor-infiltrating immune cells. Although the intensity of CD3, CD8, CD4, CD20, and CD163 in tumor tissues remained constant regardless of membrane CD95L expression, tumors in patients with HGSOC with s-CD95L levels ≥516 pg/mL showed increased infiltration by CD3+ T cells (P = 0.001), comprising both cytotoxic CD8+ (P = 0.01) and CD4+ (P = 0.0062) cells including FoxP3+ regulatory T cells (P = 0.0044). Also, the number of tumor-infiltrating CD20+ B cells (P = 0.0094) increased in these patients. Multivariate analyses revealed that low s-CD95L concentrations [6,000 CD3+ cells (HR, 0.34; 95% CI, 0.15–0.79) was a good prognostic factor. Thus, low levels of s-CD95L ( Implications: Serum s-CD95L is correlated with a number of tumor-infiltrating immune cells in HGSOC and could be used as a noninvasive marker of tumor immune infiltration to select patients referred for immunotherapy trials that evaluate checkpoint inhibitor treatment.
Published: 2019
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26. Oxidized products of α-linolenic acid negatively regulate cellular survival and motility of breast cancer cells

Author: Philippe G. Frank, Jean-Marie Galano, Jorge L. Gutierrez-Pajares, Camille Oger, Céline Ben Hassen, Thierry Durand, Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), J.L.G.-P. was supported by Le Studium (Région Centre-Val de Loire, France). P.G.F. was supported by grants from INCa PLBio (2018-145), the Lipids ARD2020-Biodrug project (Région Centre-Val de Loire, France), La Ligue contre le Cancer (Indre et Loire, Loir et Cher, and Vienne), by an Academic Research Grant from the Région Centre-Val de Loire (France) and by the Canceropole Grand-Ouest (Mature project)., Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), and Frank, Philippe
Subjects: lcsh:QR1-502, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:Microbiology, 0302 clinical medicine, Cell Movement, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Cytotoxic T cell, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 2. Zero hunger, 0303 health sciences, Chemistry, Prostanoic Acids, alpha-Linolenic Acid, Cell migration, 3. Good health, 030220 oncology & carcinogenesis, MCF-7 Cells, Female, Oxidation-Reduction, medicine.drug, Cell Survival, Antineoplastic Agents, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, lipids, 03 medical and health sciences, Breast cancer, breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Humans, Doxorubicin, Viability assay, phytoprostane, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Furans, Cell adhesion, Cell Proliferation, 030304 developmental biology, Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Cell culture, Cancer research, Drug Screening Assays, Antitumor, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Despite recent advances in our understanding of the biological processes leading to the development and progression of cancer, there is still a need for new and effective agents to treat this disease. Phytoprostanes (PhytoPs) and phytofurans (PhytoFs) are non-enzymatically oxidized products of &alpha, linolenic acid that are present in seeds and vegetable oils. They have been shown to possess anti-inflammatory and apoptosis-promoting activities in macrophages and leukemia cells, respectively. In this work, seven PhytoPs (PP1&ndash, PP7) and one PhytoFs (PF1) were evaluated for their cytotoxic, chemosensitization, and anti-migratory activities using the MCF-7 and MDA-MB-231 breast cancer cell lines. Among the tested compounds, only three PhytoPs had a significant effect on cell viability compared to the control group: Ent-9-L1-PhytoP (PP6) decreased cell viability in both cell lines, while 16-F1t-PhytoP (PP1) and 9-L1-PhytoP (PP5) decreased viability of MCF-7 and MDA-MB-231 cells, respectively. When combined with a sub-cytotoxic dose of doxorubicin, these three PhytoPs displayed significantly enhanced cytotoxic effects on MCF-7 cells while the chemotherapeutic drug alone had no effect. In cellular motility assays, Ent-9-(RS)-12-epi-ST-&Delta, 10-13-PhytoF could significantly inhibit cellular migration of MDA-MB-231 cells. In addition, Ent-9-(RS)-12-epi-ST-&Delta, 10-13-PhytoF also enhanced cellular adhesion of MDA-MB-231 cells.
Published: 2019
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27. A variant erythroferrone disrupts iron homeostasis in SF3B1 -mutated myelodysplastic syndrome

Author: Lionel Ades, Sabrina Bondu, Aspasia Stamatoullas, François Guillonneau, Zoubida Karim, Thomas Cluzeau, Mathilde Hunault, Raphaël Margueron, Elizabeta Nemeth, Grace Jung, Olivier Kosmider, Michel Wassef, Nathalie Droin, Ismael Boussaid, Carine Lefevre, Patrick Mayeux, Emmanuel Gyan, Susann Winter, Alexandre Houy, Anne-Sophie Alary, Alice Rousseau, Léon Kautz, Didier Bouscary, Thibaud Lefebvre, Valeria Santini, Marc-Henri Stern, Tomas Ganz, Abderrahmane Bousta, Uwe Platzbecker, Hervé Puy, Samar Alsafadi, Anne Sophie Kubasch, Prunelle Perrier, David Rombaut, Sophie Park, Andrea Toma, Sophie Kaltenbach, Nicolas Cagnard, Michaela Fontenay, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], University of California [Los Angeles] (UCLA), University of California (UC), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Université Paris Descartes - Paris 5 (UPD5)-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 de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 Gustave Roussy (IGR), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de bioinformatique [Université de Paris], Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Technische Universität Dresden = Dresden University of Technology (TU Dresden), University Hospital Leipzig, Università degli Studi di Firenze = University of Florence (UniFI), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), ERL 7001 LNOx (Leukemic Niche & redOx metabolism / Niche leucémique et métabolisme redOx) (LNOx), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Centre National de la Recherche Scientifique (CNRS)-Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT)-Université de Tours (UT), 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), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU), NIH U54HL119893 :(IC-INTAS), INSERM, Institut National du Cancer INCa PLBio (INCa_9290), INCa, Direction Generale de l'Offre de Soins (DGOS) of the French Ministry of Social Affairs and Health through the Programme Hospitalier de Recherche Clinique (PHRC MDS-04), (INCa-DGOS_5480), Site de Recherche Integree sur le Cancer (SIRIC) CAncer Research for PErsonalized Medicine (CARPEM) - FEDER, Canceropole Ile de France (ANR-16), (ACHN-0002-01), UCLA Center for Accelerated Innovation, ANR-16-ACHN-0002,RECERFE,Caractérisation fonctionnelle de l'érythroferrone et applications thérapeutiques.(2016), KAUTZ, Léon, Caractérisation fonctionnelle de l'érythroferrone et applications thérapeutiques. - - RECERFE2016 - ANR-16-ACHN-0002 - AAPG2016 - VALID, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California, 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)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université Nice Sophia Antipolis (... - 2019) (UNS), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Tours (UT)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Cochin [AP-HP], Institut Curie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Technische Universität Dresden (TUD), University of Florence (UNIFI), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Leukemic Niche & redOx metabolism/Niche Leucémique et Métabolisme Oxydatif (ERL7001 LNOx CNRS), Université de Tours-Université de Tours-UFR de Médecine de TOURS, Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), and Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Erythroid dysplasia, Biology, 03 medical and health sciences, Splicing factor, 0302 clinical medicine, Hepcidin, hemic and lymphatic diseases, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Myelodysplastic syndromes, fungi, Hematopoietic stem cell, food and beverages, erythroferrone, iron homeostasis , myelodysplastic syndrome, General Medicine, Erythroferrone, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Erythropoiesis, Bone marrow, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Myelodysplastic syndromes (MDS) with ring sideroblasts are hematopoietic stem cell disorders with erythroid dysplasia and mutations in the SF3B1 splicing factor gene. Patients with MDS with SF3B1 mutations often accumulate excessive tissue iron, even in the absence of transfusions, but the mechanisms that are responsible for their parenchymal iron overload are unknown. Body iron content, tissue distribution, and the supply of iron for eryth-ropoiesis are controlled by the hormone hepcidin, which is regulated by erythroblasts through secretion of the erythroid hormone erythroferrone (ERFE). Here, we identified an alternative ERFE transcript in patients with MDS with the SF3B1 mutation. Induction of this ERFE transcript in primary SF3B1-mutated bone marrow erythroblasts generated a variant protein that maintained the capacity to suppress hepcidin transcription. Plasma concentrations of ERFE were higher in patients with MDS with an SF3B1 gene mutation than in patients with SF3B1 wild-type MDS. Thus, hepcidin suppression by a variant ERFE is likely responsible for the increased iron loading in patients with SF3B1-mutated MDS, suggesting that ERFE could be targeted to prevent iron-mediated toxicity. The expression of the variant ERFE transcript that was restricted to SF3B1-mutated erythroblasts decreased in lenalidomide-responsive anemic patients, identifying variant ERFE as a specific biomarker of clonal erythropoiesis.
Published: 2019
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28. Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy

Author: Roisin M. Dwyer, Katarzyna Mnich, Qingping Zeng, Patrick Legembre, Aitor Almanza, Stephanie Greene, Anup M. Oommen, Adrienne M. Gorman, Eoghan P. McGrath, Susan E. Logue, Emma C. Madden, Brian Leuzzi, Patricia Cleary, Richard Jäger, John B. Patterson, Joanna Obacz, Florence Godey, Eric Chevet, Afshin Samali, National University of Ireland [Galway] (NUI Galway), Fosun Orinove PharmaTech Inc.[Newbury Park, CA], Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Fosun Orinove PharmaTech Inc.[Jiangsu], University of Applied Sciences [Rheinbach], NUI Galway, Irish Government's Programme for Research in Third Level Institutions, Cycles 4 and 5, National Development Plan 2007-2013, Institut National du Cancer (INCa) [PLBIO 2017-148], Irish Cancer Society Scholarship [CRS11CLE], Thomas Crawford Hayes Funds of NUIG, Irish Research Council Employment Based Programme Scholarship Scheme [BPPG/2014/57], Irish Research Council Fellowship [GOIPD/2014/53], Breast Cancer Campaign grant [2010NovPR13, 2015MaySP550], Health Research Board [HRA-POR-2014-643], Belgium Grant [IAP 7/32], Science Foundation Ireland (SFI) grant - European Regional Development Fund [13/RC/2073], SFI Starting Investigator Grant [15/SIRG/3528], EU H2020 MSCA [ITN-675448, RISE-734749], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent
Subjects: 0301 basic medicine, Programmed cell death, Paclitaxel, RNase P, Science, Mice, Nude, General Physics and Astronomy, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Protein Serine-Threonine Kinases, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, [SDV.CAN] Life Sciences [q-bio]/Cancer, RNA interference, Cell Line, Tumor, ddc:570, Antineoplastic Combined Chemotherapy Protocols, Endoribonucleases, Animals, Humans, Medicine, Enzyme Inhibitors, lcsh:Science, Multidisciplinary, business.industry, Gene Expression Profiling, Endoplasmic reticulum, HEK 293 cells, General Chemistry, Xenograft Model Antitumor Assays, 3. Good health, Gene Expression Regulation, Neoplastic, CXCL1, HEK293 Cells, 030104 developmental biology, chemistry, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cancer research, Unfolded protein response, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Female, RNA Interference, lcsh:Q, business
Abstract: Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe stress, to cell death. Here we demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGFβ2 in TNBC cells. We further show that the chemotherapeutic drug, paclitaxel, enhances IRE1 RNase activity and this contributes to paclitaxel-mediated expansion of tumor-initiating cells. In a xenograft mouse model of TNBC, inhibition of IRE1 RNase activity increases paclitaxel-mediated tumor suppression and delays tumor relapse post therapy. We therefore conclude that inclusion of IRE1 RNase inhibition in therapeutic strategies can enhance the effectiveness of current chemotherapeutics., IRE1/XBP-1 activation has a major role in Triple negative breast cancer (TNBC). Here, the authors show that inhibition of IRE1’s RNase activity attenuates autocrine and paracrine signaling of pro-tumorigenic cytokines and synergizes with paclitaxel to confer potent anti-tumor effects in TNBC.
Published: 2018
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29. Disrupting the CD95-PLC gamma 1 interaction prevents Th17-driven inflammation

Author: Patrick Blanco, Amanda Poissonnier, Nicolas Levoin, Patrick Legembre, Lucie Morere, Pierre van de Weghe, Guennadi Kozlov, Sophie Martin, Isabelle Douchet, Ha Thanh Nguyen, Estibaliz Lazaro, Daniel Best, Raphael Pineau, Melissa Thomas, Jean-Philippe Guégan, Mickael Jean, Thomas Ducret, Pierre Vacher, Florence Jouan, Kalle Gehring, CRLCC Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Bioprojet-Biotech, McGill University = Université McGill [Montréal, Canada], Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Université de Bordeaux (UB), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, INCa PLBIO, Ligue Contre le Cancer, Fondation ARC, ANR PRCE, Fondation Arthritis, Canadian Institutes of Health Research [FRN-156276], Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], and UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Lupus erythematosus, biology, Chemistry, Peptidomimetic, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Biology, Fas receptor, medicine.disease, 3. Good health, Cell biology, 03 medical and health sciences, 030104 developmental biology, biology.protein, medicine, HIV Protease Inhibitor, Ritonavir, FADD, medicine.symptom, Signal transduction, Molecular Biology, medicine.drug
Abstract: International audience; CD95L is a transmembrane ligand (m-CD95L) that is cleaved by metalloproteases to release a soluble ligand (s-CD95L). Unlike m-CD95L, interaction between s-CD95L and CD95 fails to recruit caspase-8 and FADD to trigger apoptosis and instead induces a Ca2+ response via docking of PLC gamma 1 to the calcium-inducing domain (CID) within CD95. This signaling pathway induces accumulation of inflammatory Th17 cells in damaged organs of lupus patients, thereby aggravating disease pathology. A large-scale screen revealed that the HIV protease inhibitor ritonavir is a potent disruptor of the CD95-PLC gamma 1 interaction. A structure-activity relationship approach highlighted that ritonavir is a peptidomimetic that shares structural characteristics with CID with respect to docking to PLC gamma 1. Thus, we synthesized CID peptidomimetics abrogating both the CD95-driven Ca2+ response and transmigration of Th17 cells. Injection of ritonavir and the CID peptidomimetic into lupus mice alleviated clinical symptoms, opening a new avenue for the generation of drugs for lupus patients.
Published: 2018
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30. Alterations of EDEM1 functions enhance ATF6 pro-survival signaling

Author: Eric Chevet, Gwénaële Jégou, Laure Saas, Florence Jouan, Raphael Pineau, Tony Avril, Arisa Higa, Olivier Pluquet, Alexandra Papaioannou, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Mécanismes de la Tumorigénèse et Thérapies Ciblées - UMR 8161 (M3T), 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 National de la Recherche Scientifique (CNRS), Equipe Labellisée 2018, La Fondation pour la Recherche Médicale, ITN-675448, EU H2020 MSCA, INCa_7981, Institut National du Cancer, INCa_5869, Institut National du Cancer, INCa_PLBIO_ 2015-111, Institut National du Cancer, ICGC0, Institut National du Cancer, INCa_PLBIO_2017, Institut National du Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: 0301 basic medicine, Proteases, Carcinoma, Hepatocellular, Activating transcription factor, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biochemistry, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Transcription (biology), Tumor Cells, Cultured, Gene silencing, Humans, cancer, Molecular Biology, Cell Proliferation, Chemistry, ATF6, Endoplasmic reticulum, Liver Neoplasms, Membrane Proteins, Cell Biology, unfolded protein response, Golgi apparatus, Endoplasmic Reticulum Stress, Cell biology, Activating Transcription Factor 6, 030104 developmental biology, 030220 oncology & carcinogenesis, endoplasmic reticulum quality control, Mutation, symbols, Unfolded protein response, Signal Transduction
Abstract: International audience; Activating transcription factor 6 alpha (referred to as ATF6 hereafter) is an endoplasmic reticulum (ER)-resident glycoprotein and one of the three sensors of the unfolded protein response (UPR). Upon ER stress, ATF6 is exported to the Golgi complex where it is cleaved by the S1P and S2P proteases thus releasing ATF6 cytosolic fragment and leading to the transcription of ATF6 target genes. In this study, we performed a phenotypic small-interfering RNA (siRNA) screening to better characterize the ER mechanisms involved in ATF6 activation upon ER stress. This revealed that silencing of ER-degradation-enhancing alpha-mannosidase-like protein-1 (EDEM1) increased the bioavailability of ER stress-induced ATF6 export to the Golgi complex through the stabilization of the natively unstable ATF6 protein. Moreover, we characterized a somatic variant of EDEM1 (N198I) found in hepatocellular carcinoma that alters ATF6 signaling and might provide a selective advantage to the transforming cells. Hence, our work confirms the natively unstable nature of ATF6 and links this property to potentially associated pro-oncogenic functions.
Published: 2018
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31. High-salt Recovered Sequences are associated with the active chromosomal compartment and with large ribonucleoprotein complexes including nuclear bodies

Author: Baudement, Marie, Cournac, Axel, Court, Franck, Seveno, Marie, Parrinello, Hugues, Reynes, Christelle, Sabatier, Robert, Bouschet, Tristan, Yi, Zhou, Sallis, Sephora, Tancelin, Mathilde, Rebouissou, Cosette, Cathala, Guy, Lesne, Annick, Mozziconacci, Julien, Journot, Laurent, Forné, Thierry, Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), BioCampus Montpellier (BCM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), 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), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Laboratoire de Physique Théorique des Liquides (LPTL), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Théorique de la Matière Condensée (LPTMC), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), AFM-Téléthon contrat N°21024, Institut National du Cancer (INCa) PLBIO 2012-129, ANR-16-CE15-0018,CHRODYT,Différenciation des lymphocytes T et plasticité de la chromatine(2016), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Matière et Systèmes Complexes (MSC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-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), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, High-salt Recovered Sequences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Phase separation, super-enhancers, nuclear bodies, Active chromosomal compartment, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2018
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32. IFN-III is selectively produced by cDC1 and predicts good clinical outcome in breast cancer

Author: Jenny Valladeau-Guilemond, Elisa Gobbini, Christophe Sajous, Vincent Ollion, Céline Rodriguez, Olivier Tredan, Margaux Hubert, Isabelle Treilleux, Marc Dalod, Justine Berthet, Bertrand Dubois, Christophe Caux, Janice Kielbassa, Coline Couillault, Anne-Claire Doffin, Thien-Phong Vu Manh, Nathalie Bendriss-Vermare, 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Développement Cancer et Thérapies Ciblées [Lyon] (LabEx DEVweCAN), Université de Lyon, Institut de Recherche en Mathématiques, Interactions et Applications (Labex_IRMIA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), SERM, INCA (PLBIO INCa_4508and PLBIO INCa_11155), ANRS, ARC, Ligue contre le Cancer (Régionale Auvergne-Rhône-Alpes et Saône-et-Loire, Comité de la Savoie), and la Région Rhône-Alpes Auvergne (IRICE), 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 [Grenoble] (CHU), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Fondation Synergie Lyon Cancer [Lyon]
Subjects: 0301 basic medicine, Chemokine, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Immunology, Breast Neoplasms, Interferon Lambda, 03 medical and health sciences, 0302 clinical medicine, Immune system, Breast cancer, Interferon, Medicine, Cytotoxic T cell, Humans, biology, business.industry, General Medicine, Immunotherapy, Dendritic Cells, medicine.disease, Immunity, Innate, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, TLR3, biology.protein, Cancer research, Female, Interferons, business, Conventional Dendritic Cell, medicine.drug
Abstract: International audience; Dendritic cells play a key role in the orchestration of antitumor immune responses. The cDC1 (conventional dendritic cell 1) subset has been shown to be essential for antitumor responses and response to immunotherapy, but its precise role in humans is largely unexplored. Using a multidisciplinary approach, we demonstrate that human cDC1 play an important role in the antitumor immune response through their capacity to produce type III interferon (IFN-λ). By analyzing a large cohort of breast primary tumors and public transcriptomic datasets, we observed specific production of IFN-λ1 by cDC1. In addition, both IFN-λ1 and its receptor were associated with favorable patient outcomes. We show that IFN-III promotes a TH1 microenvironment through increased production of IL-12p70, IFN-γ, and cytotoxic lymphocyte–recruiting chemokines. Last, we showed that engagement of TLR3 is a therapeutic strategy to induce IFN-III production by tumor-associated cDC1. These data provide insight into potential IFN- or cDC1-targeting antitumor therapies.
Published: 2018
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33. Dual IRE1 RNase functions dictate glioblastoma development

Author: Stéphanie Lhomond, Tony Avril, Nicolas Dejeans, Konstantinos Voutetakis, Dimitrios Doultsinos, Mari McMahon, Raphaël Pineau, Joanna Obacz, Olga Papadodima, Florence Jouan, Heloise Bourien, Marianthi Logotheti, Gwénaële Jégou, Néstor Pallares‐Lupon, Kathleen Schmit, Pierre‐Jean Le Reste, Amandine Etcheverry, Jean Mosser, Kim Barroso, Elodie Vauléon, Marion Maurel, Afshin Samali, John B Patterson, Olivier Pluquet, Claudio Hetz, Véronique Quillien, Aristotelis Chatziioannou, Eric Chevet, Université de Bordeaux (UB), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Theoretical and Physical Chemistry Institute NHRF, National Hellenic Research Foundation, 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 ), National University of Ireland [Galway] (NUI Galway), Mécanismes de la Tumorigénèse et Thérapies Ciblées - UMR 8161 (M3T), 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 National de la Recherche Scientifique (CNRS), Universidad de Santiago de Chile [Santiago] (USACH), Institut National du Cancer (INCa [PLBIO 2017-148, PLBIO 2015-111, INCA_ 7981], La Ligue Contre le Cancer (Comite des Landes, LARGE project), PHC Maimonide, EU H MSCA [ITN-675448, RISE-734749], Region Bretagne 'AAP CRITT sante', French government, Fondation pour la Recherche Medicale, Fondation de France, Region Bretagne, Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1)
Subjects: Medicine (General), Carcinogenesis, QH426-470, er stress, Chromatin, Epigenetics, Genomics & Functional Genomics, 0302 clinical medicine, glioma, Editorial Note, Tumor Microenvironment, ComputingMilieux_MISCELLANEOUS, Research Articles, 0303 health sciences, Brain Neoplasms, regulated IRE1‐dependent decay, unfolded protein response, Neoplasm Proteins, requiring enzyme 1-alpha, XBP1, Gene Expression Regulation, Neoplastic, endoplasmic reticulum, Phenotype, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Molecular Medicine, regulated IRE1-dependent decay, xbp-1 messenger-rna, Corrigendum, Signal Transduction, Research Article, RNA Splicing, ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION, [SDV.CAN]Life Sciences [q-bio]/Cancer, IRE1, Protein Serine-Threonine Kinases, Models, Biological, 03 medical and health sciences, R5-920, Cell Line, Tumor, Endoribonucleases, expression, Genetics, Humans, [CHIM]Chemical Sciences, cancer, RNA, Messenger, 030304 developmental biology, pathway, endoplasmic-reticulum, Mutation, Glioblastoma, 030217 neurology & neurosurgery, ire1-alpha, Neuroscience
Abstract: International audience; Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1 alpha (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1-dependent decay (RIDD) of RNA. Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1-dependent gene expression signatures that were confronted to human GBM transcriptomes. This approach allowed us to demonstrate the antagonistic roles of XBP1 mRNA splicing and RIDD on tumor outcomes, mainly through selective remodeling of the tumor stroma. This study provides the first demonstration of a dual role of IRE1 downstream signaling in cancer and opens a new therapeutic window to abrogate tumor progression.
Published: 2018
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34. Low-Protein Diet Induces IRE1α-Dependent Anticancer Immunosurveillance

Author: Konstantinos Voutetakis, Els Verhoeyen, Jean-Ehrland Ricci, Laura Mondragón, Cynthia Lebeaupin, Jozef P. Bossowski, Camila Rubio-Patiño, Aristotelis Chatziioannou, François Fenaille, Eric Chevet, Johanna Chiche, Thierry Passeron, Lazaro Emilio Aira, Tony Avril, Gian Marco De Donatis, Sandrine Marchetti, Rana Mhaidly, Florence Castelli, John B. Patterson, Patricia Lamourette, Elodie Villa, Emeline Chu-Van, Béatrice Bailly-Maitre, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), MetaboHUB, Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Canceropôle PACA, Fondation pour la Recherche Médicale, La Ligue contre le Cancer, EU H2020, Agence Nationale de la Recherche, Ligue Contre le Cancer, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Association Française pour l'Etude du Foie, Institut National de la Santé et de la Recherche Médicale, Société Francophone du Diabète, Fondation ARC pour la Recherche sur le Cancer, INCa PLBIO: 2015-111, Institut National Du Cancer, Institut National du Cancer and Conseil Régional PACA, French Ministry of Research, ANR-11-INBS-0010, MetaboHUB, 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), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-11-INBS-0010,METABOHUB,Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation(2011)
Subjects: 0301 basic medicine, Lymphoma, Physiology, medicine.medical_treatment, Melanoma, Experimental, immunosurveillance, UPR, CD8-Positive T-Lymphocytes, anti-tumor immunity, Mice, Immunologic Surveillance, Mice, Inbred BALB C, 3. Good health, Immunosurveillance, Cytokine, RIG1, Female, Colorectal Neoplasms, ER stress, RNA Helicases, Signal Transduction, Antigen-Presenting Cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Protein Serine-Threonine Kinases, Biology, Lymphocyte Depletion, 03 medical and health sciences, Immune system, Low-protein diet, Cell Line, Tumor, Endoribonucleases, Diet, Protein-Restricted, medicine, Animals, cancer, [CHIM]Chemical Sciences, Molecular Biology, Cancer, dietary restriction, Neoplasms, Experimental, Cell Biology, IRE1α, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Cancer cell, Unfolded Protein Response, Unfolded protein response, Cancer research, diet, CD8
Abstract: International audience; Dietary restriction (DR) was shown to impact on tumor growth with very variable effects depending on the cancer type. However, how DR limits cancer progression remains largely unknown. Here, we demonstrate that feeding mice a low-protein (Low PROT) isocaloric diet but not a low-carbohydrate (Low CHO) diet reduced tumor growth in three independent mouse cancer models. Surprisingly, this effect relies on anticancer immunosurveillance, as depleting CD8 T cells, antigen-presenting cells (APCs), or using immunodeficient mice prevented the beneficial effect of the diet. Mechanistically, we established that a Low PROT diet induces the unfolded protein response (UPR) in tumor cells through the activation of IRE1α and RIG1 signaling, thereby resulting in cytokine production and mounting an efficient anticancer immune response. Collectively, our data suggest that a Low PROT diet induces an IRE1α-dependent UPR in cancer cells, enhancing a CD8-mediated T cell response against tumors.
Published: 2018
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35. The role of the anti-aging protein klotho in IGF-1 signaling and reticular calcium leak: impact on the chemosensitivity of dedifferentiated liposarcomas

Author: Delcroix, V., Mauduit, O., Tessier, Nolwenn, Montillaud, A., Lesluyes, T., Ducret, T., Chibon, F., Van Coppenolle, Fabien, Ducreux, Sylvie, Vacher, P., Département des Sciences de la Santé, Université de Bordeaux, Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale (INSERM), Department de Pathologie, Institut Bergonié, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, INCa PLBIO, Ligue Contre le Cancer (Comite des Pyrénées Atlantiques), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER-UNICANCER, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), ProdInra, Archive Ouverte, UNICANCER, Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2, Unité de Biotechnologie, Biocatalyse et Biorégulation (U3B), Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), and Institut Bergonié - CRLCC Bordeaux
Subjects: insulin, proliferation, [SDV]Life Sciences [q-bio], klotho, TRPC6, soft-tissue sarcomas, [SDV.CAN]Life Sciences [q-bio]/Cancer, channels, lcsh:RC254-282, Article, stress, [SDV.CAN] Life Sciences [q-bio]/Cancer, pancreatic-cancer, expression, cancer, translocon, gemcitabine resistance, calcium, gemcitabine, stress-induced apoptosis, tumor-suppressor, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, ERK, Oncology, er, liposarcoma, IGF-1, ER stress
Abstract: By inhibiting Insulin-Like Growth Factor-1-Receptor (IGF-1R) signaling, Klotho (KL) acts like an aging- and tumor-suppressor. We investigated whether KL impacts the aggressiveness of liposarcomas, in which IGF-1R signaling is frequently upregulated. Indeed, we observed that a higher KL expression in liposarcomas is associated with a better outcome for patients. Moreover, KL is downregulated in dedifferentiated liposarcomas (DDLPS) compared to well-differentiated tumors and adipose tissue. Because DDLPS are high-grade tumors associated with poor prognosis, we examined the potential of KL as a tool for overcoming therapy resistance. First, we confirmed the attenuation of IGF-1-induced calcium (Ca2+)-response and Extracellular signal-Regulated Kinase 1/2 (ERK1/2) phosphorylation in KL-overexpressing human DDLPS cells. KL overexpression also reduced cell proliferation, clonogenicity, and increased apoptosis induced by gemcitabine, thapsigargin, and ABT-737, all of which are counteracted by IGF-1R-dependent signaling and activate Ca2+-dependent endoplasmic reticulum (ER) stress. Then, we monitored cell death and cytosolic Ca2+-responses and demonstrated that KL increases the reticular Ca2+-leakage by maintaining TRPC6 at the ER and opening the translocon. Only the latter is necessary for sensitizing DDLPS cells to reticular stressors. This was associated with ERK1/2 inhibition and could be mimicked with IGF-1R or MEK inhibitors. These observations provide a new therapeutic strategy in the management of DDLPS.
Published: 2018
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36. Nonapoptotic functions of Fas/CD95 in the immune response

Author: Jean-Philippe Guégan, Patrick Legembre, Jonchère, Laurent, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), INCa PLBIO, Fondation ARC, La Ligue contre le Cancer (Comités d’Ille-et-Vilaine/du Morbihan/des Cotes d’Armor/du Finistere/du Maine et Loire), Canceropole GrandOuest, Region Bretagne, Rennes Metropole, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Lymphocyte Activation, migration, Biochemistry, PI3K, Fas ligand, caspase-8, immune response, Neoplasms, [CHIM] Chemical Sciences, Receptor, Systemic lupus erythematosus, Lymphopoiesis, apoptosis, Fas receptor, 3. Good health, Signal transduction, Signal Transduction, Fas Ligand Protein, FLIP, T lymphocytes, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Caspase 8, 03 medical and health sciences, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, [CHIM]Chemical Sciences, fas Receptor, Molecular Biology, Immunity, Models, Immunological, Membrane Proteins, Cell Biology, Dendritic Cells, lupus, Fas, medicine.disease, Lymphocyte Subsets, 030104 developmental biology, Solubility, inflammation, Autoimmune lymphoproliferative syndrome, Multiprotein Complexes, Immunology, Cancer research, Protein Multimerization, Immunologic Memory
Abstract: International audience; CD95 (also known as Fas) is a member of the tumor necrosis factor receptor (TNFR) superfamily. Its cognate ligand, CD95L, is implicated in immune homeostasis and immune surveillance. Mutations in this receptor are associated with a loss of apoptotic signaling and have been detected in an autoimmune disorder called autoimmune lymphoproliferative syndrome (ALPS) type Ia, which shares some clinical features with systemic lupus erythematosus (SLE). In addition, deletions and mutations of CD95 have been described in many cancers, which led researchers to initially classify this receptor as a tumor suppressor. More recent data demonstrate that CD95 engagement evokes nonapoptotic signals that promote inflammation and carcinogenesis. Transmembrane CD95L (m-CD95L) can be cleaved by metalloproteases, releasing a soluble ligand (s-CD95L). Soluble and membrane-bound CD95L show different stoichiometry (homotrimer versus multimer of homotrimers, respectively), which differentially affects CD95-mediated signaling through molecular mechanisms that remain to be elucidated. This review discusses the biological roles of CD95 in light of recent experiments addressing how a death receptor can trigger both apoptotic and nonapoptotic signaling pathways.
Published: 2018
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37. The MeLiM Minipig: An Original Spontaneous Model to Explore Cutaneous Melanoma Genetic Basis

Author: Bourneuf, Emmanuelle, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, INCa PLBIO, Ligue Nationale contre le Cancer PRE, INRA, and CEA
Subjects: porcine model, predisposition genes, cutaneous melanoma, QTL, endogenous retrovirus, [SDV]Life Sciences [q-bio], Genetics, Molecular Medicine, Review, Genetics (clinical)
Abstract: Melanoma is the deadliest skin cancer and is a major public health concern with a growing incidence worldwide. As for other complex diseases, animal models are needed in order to better understand the mechanisms leading to pathology, identify potential biomarkers to be used in the clinics, and eventually molecular targets for therapeutic solutions. Cutaneous melanoma, arising from skin melanocytes, is mainly caused by environmental factors such as UV radiation; however a significant genetic component participates in the etiology of the disease. The pig is a recognized model for spontaneous development of melanoma with features similar to the human ones, followed by a complete regression and a vitiligo-like depigmentation. Three differentpig models (MeLiM, Sinclair, and MMS-Troll) have been maintained through the last decades, and different genetic studies have evidenced a complex inheritance of the disease. As in humans, pigmentation seems to play a prominent role, notably through MC1R and MITF signaling. Conversely, cell cycle genes as CDKN2A and CDK4 have been excluded as predisposing for melanoma in MeLiM. So far, only sparse studies have focused on somatic changes occurring during oncogenesis, and have revealed major cytological changes and a potential dysfunction of the telomere maintenance system. Finally, the spontaneous tumor progression and regression occurring in these models could shed light on the interplay between endogenous retroviruses, melanomagenesis, and adaptive immune response.
Published: 2017
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38. BCL-XL directly modulates RAS signalling to favour cancer cell stemness

Author: Carné Trécesson, Sophie de, Souazé, Frédérique, Basseville, Agnès, Bernard, Anne-Charlotte, Pécot, Jessie, Lopez, Jonathan, Bessou, Margaux, Sarosiek, Kristopher A., Letai, Anthony, Barillé-Nion, Sophie, Valo, Isabelle, Coqueret, Olivier, Guette, Catherine, Campone, Mario, Gautier, Fabien, Juin, Philippe Paul, Bernardo, Elizabeth, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), 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), Service de Biochimie et Biologie moléculaire [CH Lyon Sud], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Dana-Farber Cancer Institute [Boston, USA], Harvard Medical School [Boston] (HMS), Département de Biopathologie [Angers], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Senescence Escape and Soluble Markers of Cancer Progression (CRCINA-ÉQUIPE 12), Dr S. de Carné Trécesson was supported by Institut National du Cancer, Dr J. Pécot by Ministère de la Recherche et de l’Enseignement Supérieur and Dr A. Basseville by Fondation de France. This work was supported by Canceropole Grand Ouest (CIC project 2010–2012, MATURE project 2017–18), ARC (R15083NN), Fondation de France (2015) and INCA PLBio (R12134NN) to PJ, Ligue Grand Ouest (R13137) to SCT and PJ and Fondation de France (2017) to AB., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Proteomics, Science, bcl-X Protein, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Apoptosis, Breast Neoplasms, Article, Mass Spectrometry, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Animals, Humans, lcsh:Science, HMGA2 Protein, Gene Expression Regulation, Neoplastic, Phenotype, Drug Resistance, Neoplasm, MCF-7 Cells, Neoplastic Stem Cells, ras Proteins, lcsh:Q, Female, Neoplasm Recurrence, Local, Proto-Oncogene Proteins c-fos, Plasmids, Signal Transduction
Abstract: In tumours, accumulation of chemoresistant cells that express high levels of anti-apoptotic proteins such as BCL-XL is thought to result from the counter selection of sensitive, low expresser clones during progression and/or initial treatment. We herein show that BCL-XL expression is selectively advantageous to cancer cell populations even in the absence of pro-apoptotic pressure. In transformed human mammary epithelial cells BCL-XL favours full activation of signalling downstream of constitutively active RAS with which it interacts in a BH4-dependent manner. Comparative proteomic analysis and functional assays indicate that this is critical for RAS-induced expression of stemness regulators and maintenance of a cancer initiating cell (CIC) phenotype. Resistant cancer cells thus arise from a positive selection driven by BCL-XL modulation of RAS-induced self-renewal, and during which apoptotic resistance is not necessarily the directly selected trait., BCL-XL provides a survival advantage to cancer cells even in the absence of apoptotic pressures. In this study, the authors show that BCL-XL interacts with RAS in a BH4-dependent manner and regulates RAS-mediated activation of pathways involved in the stemness feature of breast cancer cells.
Published: 2017
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39. CD95/Fas, Non-Apoptotic Signaling Pathways, and Kinases

Author: Le Gallo, Matthieu, Poissonnier, Amanda, Blanco, Patrick, Legembre, Patrick, Centre Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), INCa PLBIO, Fondation ARC, La Ligue contre le Cancer, Region Bretagne, and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: endothelium, Immunology, apoptosis, tyrosine kinase, [CHIM]Chemical Sciences, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, lupus metastasis, Fas, migration, FasL
Abstract: International audience; Endothelial cells lining new blood vessels that develop during inflammatory disorders or cancers act as doors that either allow or block access to the tumor or inflamed organ. Recent data show that these endothelial cells in cancer tissues and inflamed tissues of lupus patients overexpress CD95L, the biological role of which is a subject of debate. The receptor CD95 (also named Fas or apoptosis antigen 1) belongs to the tumor necrosis factor (TNF) receptor superfamily. Its cognate ligand, CD95L, is implicated in immune homeostasis and immune surveillance. Because mutations of this receptor or its ligand lead to autoimmune disorders such as systemic lupus erythematosus (SLE) and cancers, CD95 and CD95L were initially thought to play a role in immune homeostasis and tumor elimination via apoptotic signaling pathways. However, recent data reveal that CD95 also evokes non-apoptotic signals, promotes inflammation, and contributes to carcinogenesis; therefore, it is difficult to dissect its apoptotic effects from its non-apoptotic effects during pathogenesis of disease. CD95L is cleaved by metalloproteases and so exists in two different forms: a transmembrane form and a soluble ligand (s-CD95L). We recently observed that the soluble ligand is overexpressed in serum from patients with triple-negative breast cancer or SLE, in whom it contributes to disease severity by activating non-apoptotic signaling pathways and promoting ss the roleeither metastatic dissemination or accumulation of certain T cell subsets in damaged organs. Here, we discus of CD95 in modulating immune functions via induction of mainly non-apoptotic signaling pathways.
Published: 2017
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40. Myeloid-derived suppressor cell, arginase-1, IL-17 and cl-CD95L: an explosive cocktail in lupus?

Author: Patrick Legembre, Robin J. Flynn, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), INCa PLBIO, Ligue Contre le Cancer et Fondation ARC, and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, CD14, CD33, Population, education, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, 03 medical and health sciences, immune system diseases, Medicine, skin and connective tissue diseases, education.field_of_study, Systemic lupus erythematosus, biology, business.industry, General Medicine, medicine.disease, 3. Good health, Arginase, 030104 developmental biology, Integrin alpha M, Immunology, biology.protein, Myeloid-derived Suppressor Cell, Interleukin 17, business
Abstract: Expansion of myeloid-derived suppressor cells (MDSCs) has been documented in some murine models and patients with autoimmune diseases, but the exact role of MDSCs in this process remains largely unknown. The current study investigates this question in patients with systemic lupus erythematosus (SLE). Patients with active SLE showed a significant increase in HLA-DR−CD11b+CD33+ MDSCs, including both CD14+CD66b− monocytic and CD14−CD66b+ granulocytic MDSCs, in the peripheral blood compared to healthy controls (HCs). The frequency of MDSCs was positively correlated with the levels of serum arginase-1 (Arg-1) activity, T helper 17 (TH17) responses, and disease severity in SLE patients. Consistently, in comparison with MDSCs from HCs, MDSCs from SLE patients exhibited significantly elevated Arg-1 production and increased potential to promote TH17 differentiation in vitro in an Arg-1–dependent manner. Moreover, in a humanized SLE model, MDSCs were essential for the induction of TH17 responses and the associated renal injuries, and the effect of MDSCs was Arg-1–dependent. Our data provide direct evidence demonstrating a pathogenic role for MDSCs in human SLE. This study also provides a molecular mechanism of the pathogenesis of SLE by demonstrating an Arg-1–dependent effect of MDSCs in the development of TH17 cell–associated autoimmunity, and suggests that targeting MDSCs or Arg-1 may offer potential therapeutic strategies for the treatment of SLE and other TH17 cell–mediated autoimmune diseases.
Published: 2017
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41. Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism

Author: François Vergez, Marine Fraisse, Nicolas Broin, Thomas Farge, Robin L. Perry, Jean-Emmanuel Sarry, Audrey Sarry, Suzanne Tavitian, Stéphanie Cassant-Sourdy, Mayumi Sugita, Laetitia K. Linares, Jason S. Iacovoni, Claudie Bosc, Olivier Duchamp, Gwenn Danet-Desnoyers, Fabienne De Toni, Sarah J. Scotland, Y Barreira, Pierre Hirsch, Emmanuel Griessinger, Estelle Saland, Camille Montersino, Rémy Castellano, Héléna Boutzen, Nizar Serhan, Laurent Vallar, Martin Carroll, Christian Recher, Moshen Hosseini, Yves Collette, Lara Gales, François Delhommeau, Marion David, Marie-Laure Nicolau-Travers, Jean-Charles Portais, Nesrine Aroua, Lucille Stuani, Clément Larrue, Tony Kaoma, Tony Lionel Palama, Mary A. Selak, Barbara Garmy-Susini, Virginie Féliu, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania [Philadelphia], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Oncology, University Hospital-Hälsouniversitetet Universitetssjukhuset, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), U1065 Centre Méditerranéen de Médecine Moléculaire, Université de Nice Sophia-Antipolis (UNSA), Oncodesign, UMS006 Service d'Experimentation Animale, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S938 CDR Saint-Antoine, Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), Université Fédérale Toulouse Midi-Pyrénées, Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation ARC [SFI20121205478], Laboratoire d'Excellence Toulouse Cancer (TOUCAN) [ANR11-LABEX], Programme Hospitalo-Universitaire en Cancerologie (CAPTOR) [ANR11-PHUC0001], INCA [PLBIO 2012-105], Veterans Affairs Administration [1I01BX000918-01], NIH [1R01CA149566-01A1], Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), 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), Equipe 11-E.Moyal/C.Toulas, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie clinique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-CRLCC Henri Becquerel-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Luxembourg Institute of Health (LIH), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncodesign Inc., Oncodesign Biotechnology®, Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre Européen de Résonance Magnétique Nucléaire à Très Hauts Champs (CERMNTHC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service d'immunologie et hématologies biologiques [Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Sorbonne Université (SU)-CHU Saint-Antoine [APHP], Service d'hématologie, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncodesign [Dijon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'immunologie et hématologies biologiques [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), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Linares, Laetitia, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-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 Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), 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), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and 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)
Subjects: CD36 Antigens, 0301 basic medicine, Myeloid, cancerologie, Mitochondrion, human health, Oxidative Phosphorylation, Mice, pharmacotherapy, 0302 clinical medicine, protéine mitochondriale, chimiothérapie, leucemie, Cytarabine, leukemia, Myeloid leukemia, santé humaine, Mitochondria, 3. Good health, Leukemia, Myeloid, Acute, Leukemia, medicine.anatomical_structure, Biochemistry, 030220 oncology & carcinogenesis, oncologie, oncology, Neoplastic Stem Cells, Stem cell, medicine.drug, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Downregulation and upregulation, Cell Line, Tumor, medicine, Animals, Humans, Cell Lineage, chimiothérapie, oncologie, cancerologie, approche thérapeutique, leucemie, protéine mitochondriale, santé humaine, approche thérapeutique, medicine.disease, Xenograft Model Antitumor Assays, carbohydrates (lipids), 030104 developmental biology, Drug Resistance, Neoplasm, Cell culture, Cancer research, pharmacotherapy, oncology, leukemia, human health, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Chemotherapy-resistant human acute myeloid leukemia (AML) cells are thought to be enriched in quiescent immature leukemic stem cells (LSC). To validate this hypothesis in vivo, we developed a clinically relevant chemotherapeutic approach treating patient-derived xenografts (PDX) with cytarabine (AraC). AraC residual AML cells are enriched in neither immature, quiescent cells nor LSCs. Strikingly, AraC-resistant preexisting and persisting cells displayed high levels of reactive oxygen species, showed increased mitochondrial mass, and retained active polarized mitochondria, consistent with a high oxidative phosphorylation (OXPHOS) status. AraC residual cells exhibited increased fatty-acid oxidation, upregulated CD36 expression, and a high OXPHOS gene signature predictive for treatment response in PDX and patients with AML. High OXPHOS but not low OXPHOS human AML cell lines were chemoresistant in vivo. Targeting mitochondrial protein synthesis, electron transfer, or fatty-acid oxidation induced an energetic shift toward low OXPHOS and markedly enhanced antileukemic effects of AraC. Together, this study demonstrates that essential mitochondrial functions contribute to AraC resistance in AML and are a robust hallmark of AraC sensitivity and a promising therapeutic avenue to treat AML residual disease. Significance: AraC-resistant AML cells exhibit metabolic features and gene signatures consistent with a high OXPHOS status. In these cells, targeting mitochondrial metabolism through the CD36–FAO–OXPHOS axis induces an energetic shift toward low OXPHOS and strongly enhanced antileukemic effects of AraC, offering a promising avenue to design new therapeutic strategies and fight AraC resistance in AML. Cancer Discov; 7(7); 716–35. ©2017 AACR. See related commentary by Schimmer, p. 670. This article is highlighted in the In This Issue feature, p. 653
Published: 2017
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42. CD95-Mediated Calcium Signaling Promotes T Helper 17 Trafficking to Inflamed Organs in Lupus-Prone Mice

Author: Patrick Blanco, Patrick Legembre, Paul A. Barrow, Aubin Penna, Cécile Contin-Bordes, Marine Malleter, Robin J. Flynn, Jerome Ritz, Thomas Ducret, Roselyne Viel, Florence Poizeau, Julien Seneschal, Alain Dupuy, Nathalie Rioux, Lucie Morere, Florence Jouan, Pierre Vacher, Matthieu Le Gallo, Alain Fautrel, Amanda Poissonnier, Edouard Forcade, Doriane Sanséau, Anne-Marie Vacher, Nicolas Levoin, Oncogenesis Stress Signaling (OSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), CRLCC Eugène Marquis (CRLCC), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire Bioprojet, H2P2 - Histo Pathologie Hight Precision (H2P2), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], Service d'immunologie et d'immunogénétique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2, INCa PLBIO, Ligue Contre le Cancer, INSERM Transfert, Fondation ARC, Region Bretagne, Rennes Metropole, University of Nottingham Faculty of Medicine, Biotechnology and Biological Sciences Research Council [BB/M018369/1], ANR [ANR-12-JSV2-0004-001], ANR-12-JSV2-0004,Ca-DoS,Vivre ou Mourir : Le calcium comme point de contrôle déterminant le destin d'une cellule suite à la stimulation des récepteurs de mort.(2012), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: 0301 basic medicine, Mice, Inbred MRL lpr, Lymphocyte, receptor, cd95, ligand, T-Lymphocytes, Regulatory, chemistry.chemical_compound, Mice, Sphingosine, Immunology and Allergy, Lupus Erythematosus, Systemic, Interferon gamma, Cells, Cultured, Th17 cell, Systemic lupus erythematosus, Interleukin-17, apoptosis, Fas receptor, autoimmune lymphoproliferative syndrome, 3. Good health, Cell biology, Infectious Diseases, medicine.anatomical_structure, sh3 domain, Female, Interleukin 17, Signal transduction, medicine.drug, Immunology, fas gene-mutations, Biology, 03 medical and health sciences, Interferon-gamma, Immune system, sphingosine-1 phosphate, death, medicine, Animals, Humans, Protein Interaction Domains and Motifs, Sphingosine-1-phosphate, Calcium Signaling, fas Receptor, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Phospholipase C gamma, pathway, Transendothelial and Transepithelial Migration, lupus, medicine.disease, Peptide Fragments, Disease Models, Animal, 030104 developmental biology, chemistry, inflammation, Th17 Cells, Calcium, Lysophospholipids, Transcriptome, protein
Abstract: International audience; CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase C gamma 1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway could be an attractive therapeutic approach for SLE treatment.
Published: 2016
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43. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents

Author: Michael R. Stratton, Eric Padron, Tingting Qin, Kenichi Yoshida, Eric Solary, Seishi Ogawa, Stéphanie Solier, Eric Jourdan, Serge Koscielny, Margot Morabito, William Vainchenker, Emilie Chautard, Dorothée Selimoglu-Buet, Jean-François Deleuze, Thérèse Commes, Kristen Meldi, Stéphane de Botton, Olivier Bernard, Claude Preudhomme, Pierre Fenaux, Marcel E. Dinger, Thorsten Braun, Mark J. Cowley, Bruno Quesnel, Vincent Meyer, Didier Auboeuf, François Artiguenave, Nathalie Droin, Maria E. Figueroa, Noémie Pata-Merci, Raphael Itzykson, Velimir Gayevskiy, Ludmil B. Alexandrov, Jane Merlevede, Hématopoïèse normale et pathologique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, School of Information, University of Michigan, Department of Molecular Diagnosis, Hamamatsu University School of Medicine, Kyoto University [Kyoto], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Avicenne [AP-HP], Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cellules souches normales et cancéreuses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Garvan Institute of Medical Research [Darlinghurst, Australia], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service d'Hématologie Cellulaire [Lille], The Wellcome Trust Sanger Institute [Cambridge], Los Alamos National Laboratory (LANL), H. Lee Moffitt Cancer Center and Research Institute, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), This programme was supported by grants from Ligue Nationale Contre le Cancer (équipe labellisée), Institut National du Cancer (INCa PLBIO, SIRIC SOCRATE), Institut National du Cancer and Direction Générale de l’Offre de Soins (PHRC-K 2011-182),Agence Nationale de la Recherche (Molecular Medicine in Oncology, Paris Alliance Cancer Research Institute: France Génomique National programs funded by ‘Investissements d’avenir’). J.M. was supported by the Fondation pour la Recherche Médicale (FDT20140931007)., Kyoto University, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Garvan Institute of medical research
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], General Physics and Astronomy, medicine.disease_cause, Epigenesis, Genetic, chemistry.chemical_compound, Cancer, Genetics, Aged, 80 and over, Mutation, Multidisciplinary, High-Throughput Nucleotide Sequencing, Cytidine, Leukemia, Myelomonocytic, Chronic, Middle Aged, 3. Good health, Gene Expression Regulation, Neoplastic, Biological sciences, DNA methylation, Azacitidine, Female, medicine.drug, Antimetabolites, Antineoplastic, Cell Survival, Science, Decitabine, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, medicine, Humans, Epigenetics, Allele, Alleles, Aged, Sequence Analysis, RNA, Myelodysplastic syndromes, General Chemistry, Sequence Analysis, DNA, MESH: Aged, 80 and over Alleles Antimetabolites, Antineoplastic / pharmacology* Antimetabolites, Antineoplastic / therapeutic use Azacitidine / analogs & derivatives* Azacitidine / pharmacology* Azacitidine / therapeutic use Cell Survival / drug effects* DNA Methylation / drug effects* Decitabine Epigenesis, Genetic / drug effects* Female Gene Expression Regulation, Neoplastic / drug effects* HEK293 Cells High-Throughput Nucleotide Sequencing Humans Leukemia, Myelomonocytic, Chronic / drug therapy Leukemia, Myelomonocytic, Chronic / genetics* Male Middle Aged Mutation, DNA Methylation, medicine.disease, 030104 developmental biology, HEK293 Cells, chemistry, Cancer research
Abstract: The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect., Chronic myelomonocytic leukaemia is treated with agents that modify DNA methylation but whether they have direct cytotoxic effects is unclear. Here, the authors show that cells from treated patients show marked methylation changes without altered somatic mutation burden, suggesting that cytotoxicity is not a major factor in therapeutic efficacy.
Published: 2016
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44. Efficient TGF-β/SMAD signaling in human melanoma cells associated with high c-SKI/SnoN expression

Author: Erwan Le Scolan, Alain Mauviel, Delphine Javelaud, Vasileia I. Alexaki, Léon C van Kempen, Kunxin Luo, 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), Radboud University Medical Center [Nijmegen], Department of Molecular & Cell Biology [Berkeley], University of California [Berkeley], University of California-University of California, This work was supported by the Donation Henriette et Emile Goutière, Institut National du Cancer (INCa, PLBIO 08-0126 ), Cancéropôle Ile-de- France, INSERM, CNRS, Ligue Nationale Contre le Cancer (Comité des Yvelines), and Université Paris XI (to A.M.), and by funds from NIH RO1 CA101891 (to K.L.). V.I.A. was the recipient of a Cancéropôle Ile-de-France/ Région Ile-de-France post-doctoral fellowship., University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC), and BMC, Ed.
Subjects: Cancer Research, Skin Neoplasms, Leupeptins, Nude, Skin Neoplasms/metabolism, Smad Proteins, SMAD, Mice, 0302 clinical medicine, Transforming Growth Factor beta, MESH: Up-Regulation, MESH: Animals, Neoplasm Metastasis, Smad Proteins/metabolism, Melanoma, 0303 health sciences, Tumor, MESH: Proteasome Endopeptidase Complex, Cyclin-Dependent Kinase Inhibitor p21/genetics, Intracellular Signaling Peptides and Proteins, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Up-Regulation, DNA-Binding Proteins, Intracellular Signaling Peptides and Proteins/metabolism, Oncology, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Molecular Medicine, RNA Interference, Proteasome Inhibitors, Transforming Growth Factor beta/metabolism, Cyclin-Dependent Kinase Inhibitor p21, Transcriptional Activation, MESH: Cell Line, Tumor, MESH: Melanoma, MESH: RNA Interference, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, lcsh:RC254-282, Cell Line, MESH: Cyclin-Dependent Kinase Inhibitor p21, 03 medical and health sciences, Downregulation and upregulation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Melanoma/metabolism, Cell Line, Tumor, Proto-Oncogene Proteins, MESH: Cell Proliferation, MESH: Intracellular Signaling Peptides and Proteins, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, MESH: Mice, Nude, Animals, Humans, Neoplasm Invasiveness, Leupeptins/pharmacology, Autocrine signalling, MESH: Mice, MESH: Transforming Growth Factor beta, 030304 developmental biology, Cell Proliferation, MESH: Humans, Cell growth, Research, MESH: Skin Neoplasms, SKI protein, MESH: Smad Proteins, MESH: Leupeptins, Transforming growth factor beta, MESH: Neoplasm Invasiveness, medicine.disease, MESH: Neoplasm Metastasis, MESH: Gene Knockdown Techniques, MESH: Cell Line, MESH: Proto-Oncogene Proteins, Proto-Oncogene Proteins/genetics, Cancer cell, Cancer research, biology.protein, MESH: Transcriptional Activation, human activities, DNA-Binding Proteins/genetics, Neoplasm Transplantation, MESH: Neoplasm Transplantation, MESH: DNA-Binding Proteins
Abstract: Background SKI and SnoN proteins have been shown to inhibit TGF-β signaling, acting both as transcriptional co-repressors in the cell nucleus, and as sequestrators of SMAD proteins in the cytoplasm. TGF-β, on the other hand, induces rapid, proteasome-mediated, degradation of both proteins. How elevated SKI and SnoN protein levels co-exist with active autocrine TGF-β signaling in cancer cells is yet to be understood. Results In this study, we found elevated SKI and SnoN protein levels in a panel of melanoma cell lines, as compared to normal melanocytes. There was no correlation between SKI protein content and the capacity of melanoma cells to invade Matrigel™, to form subcutaneous tumors, or to metastasize to bone after intracardiac inoculation into nude mice. Nor did we find a correlation between SKI expression and histopathological staging of human melanoma. TGF-β induced a rapid and dose-dependent degradation of SKI protein, associated with SMAD3/4 specific transcriptional response and induction of pro-metastatic target genes, partially prevented by pharmacologic blockade of proteasome activity. SKI knockdown in 1205Lu melanoma cells did not alter their invasive capacity or transcriptional responses to TGF-β, and did not allow p21 expression in response to TGF-β or reveal any growth inhibitory activity of TGF-β. Conclusions Despite high expression in melanoma cells, the role of SKI in melanoma remains elusive: SKI does not efficiently interfere with the pro-oncogenic activities of TGF-β, unless stabilized by proteasome blockade. Its highly labile nature makes it an unlikely target for therapeutic intervention.
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