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9 results on '"Jozef P. Bossowski"'

1. IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response

Author

Adriana Martinez-Turtos, Rachel Paul, Manuel Grima-Reyes, Hussein Issaoui, Adrien Krug, Rana Mhaidly, Jozef P. Bossowski, Johanna Chiche, Sandrine Marchetti, Els Verhoeyen, Eric Chevet, and Jean-Ehrland Ricci

Subjects
Cancer, UPR, IRE1α, XBP1s, RIDD, anti-cancer immunosurveillance, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

IRE1α is one of the three ER transmembrane transducers of the Unfolded Protein Response (UPR) activated under endoplasmic reticulum (ER) stress. IRE1α activation has a dual role in cancer as it may be either pro- or anti-tumoral depending on the studied models. Here, we describe the discovery that exogenous expression of IRE1α, resulting in IRE1α auto-activation, did not affect cancer cell proliferation in vitro but resulted in a tumor-suppressive phenotype in syngeneic immunocompetent mice. We found that exogenous expression of IRE1α in murine colorectal and Lewis lung carcinoma cells impaired tumor growth when syngeneic tumor cells were subcutaneously implanted in immunocompetent mice but not in immunodeficient mice. Mechanistically, the in vivo tumor-suppressive effect of overexpressing IRE1α in tumor cells was associated with IRE1α RNAse activity driving both XBP1 mRNA splicing and regulated IRE1-dependent decay of RNA (RIDD). We showed that the tumor-suppressive phenotype upon IRE1α overexpression was characterized by the induction of apoptosis in tumor cells along with an enhanced adaptive anti-cancer immunosurveillance. Hence, our work indicates that IRE1α overexpression and/or activation in tumor cells can limit tumor growth in immunocompetent mice. This finding might point toward the need of adjusting the use of IRE1α inhibitors in cancer treatments based on the predominant outcome of the RNAse activity of IRE1α.

Published
2022
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2. Parkin-Independent Mitophagy Controls Chemotherapeutic Response in Cancer Cells

Author

Elodie Villa, Emma Proïcs, Camila Rubio-Patiño, Sandrine Obba, Barbara Zunino, Jozef P. Bossowski, Romain M. Rozier, Johanna Chiche, Laura Mondragón, Joel S. Riley, Sandrine Marchetti, Els Verhoeyen, Stephen W.G. Tait, and Jean-Ehrland Ricci

Subjects
mitophagy, ARIH1, RBR-ligase, cell death, E3 ligase, Parkin-independent, chemoresistance, PINK1, lung cancer, mtKeima, Biology (General), QH301-705.5
Abstract

Mitophagy is an evolutionarily conserved process that selectively targets impaired mitochondria for degradation. Defects in mitophagy are often associated with diverse pathologies, including cancer. Because the main known regulators of mitophagy are frequently inactivated in cancer cells, the mechanisms that regulate mitophagy in cancer cells are not fully understood. Here, we identified an E3 ubiquitin ligase (ARIH1/HHARI) that triggers mitophagy in cancer cells in a PINK1-dependent manner. We found that ARIH1/HHARI polyubiquitinates damaged mitochondria, leading to their removal via autophagy. Importantly, ARIH1 is widely expressed in cancer cells, notably in breast and lung adenocarcinomas; ARIH1 expression protects against chemotherapy-induced death. These data challenge the view that the main regulators of mitophagy are tumor suppressors, arguing instead that ARIH1-mediated mitophagy promotes therapeutic resistance.

Published
2017
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3. Caspase 1/11 Deficiency or Pharmacological Inhibition Mitigates Psoriasis-Like Phenotype in Mice

Author

Laurent Boyer, Camila Rubio-Patiño, Johanna Chiche, Arnaud Jacquel, Maeva Gesson, Sandrine Marchetti, Pascal Colosetti, Guillaume Robert, Thierry Passeron, Jozef P. Bossowski, Jean-Ehrland Ricci, Frederic Luciano, Jean-Paul Ortonne, Laura Mondragón, Jean-Philippe Lacour, Lazaro Emilio Aira, Priscillia Lecucq-Ottavi, Sandrine Obba, R. Paul-Bellon, Béatrice Bailly-Maitre, Diogo Goncalves, Patrick Auberger, 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), 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), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Physiopathologie de la survie et de la mort cellulaire et infection virale, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Solvay Engineering Plastics, Centre méditérannéen de médecine moléculaire (C3M), 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 Nice Sophia Antipolis (1965 - 2019) (UNS), Université Côte d'Azur (UCA), 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)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR50-Université Nice Sophia Antipolis (... - 2019) (UNS), and Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)

Subjects
0301 basic medicine, Keratinocytes, Male, Biopsy, [SDV]Life Sciences [q-bio], Interleukin-1beta, Primary Cell Culture, Caspase 1, Context (language use), Dermatology, Biochemistry, Amino Acid Chloromethyl Ketones, Pathogenesis, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Psoriasis, medicine, Animals, Humans, Molecular Biology, Caspase, Cells, Cultured, Bone Marrow Transplantation, Skin, Mice, Knockout, Clinical Trials as Topic, Transplantation Chimera, biology, business.industry, Inflammasome, Cell Biology, medicine.disease, Caspase Inhibitors, Caspases, Initiator, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Tumor necrosis factor alpha, Female, business, Injections, Intraperitoneal, medicine.drug, Signal Transduction
Abstract

International audience; Inflammatory caspases, activated within the inflammasome, are responsible for the maturation and secretion of IL-1beta/IL-18. Although their expression in psoriasis was shown several years ago, little is known about the role of inflammatory caspases in the context of psoriasis. Here, we confirmed that caspases 1, 4, and 5 are activated in lesional skin from psoriasis patients. We showed in three psoriasis-like models that inflammatory caspases are activated, and accordingly, caspase 1/11 invalidation or pharmacological inhibition by Ac-YVAD-CMK (i.e., Ac-Tyr-Val-Ala-Asp-chloromethylketone) injection induced a decrease in ear thickness, erythema, scaling, inflammatory cytokine expression, and immune cell infiltration in mice. We observed that keratinocytes were primed to secrete IL-1beta when cultured in conditions mimicking psoriasis. Generation of chimeric mice by bone marrow transplantation was carried out to decipher the respective contribution of keratinocytes and/or immune cells in the activation of inflammatory caspases during psoriasis-like inflammatory response. Our data showed that the presence of caspase 1/11 in the immune system is sufficient for a fully inflammatory response, whereas the absence of caspase 1/11 in keratinocytes/fibroblasts had no impact. In summary, our study indicates that inflammatory caspases activated in immune cells are implicated in psoriasis pathogenesis.

Published
2019

4. GAPDH Expression Predicts the Response to R-CHOP, the Tumor Metabolic Status, and the Response of DLBCL Patients to Metabolic Inhibitors

Author

Vincent Delwail, Jean-Ehrland Ricci, Isabelle Peyrottes, Celine Delpech-Debiais, Sandrine Marchetti, Julie Reverso-Meinietti, Jacqueline Lehmann-Che, Gabriel Brisou, Jozef P. Bossowski, Manuel Grima-Reyes, Christiane Copie-Bergman, Camila Rubio-Patiño, Konstantina Fragaki, Eric de Kerviler, Véronique Paquis-Flucklinger, Thierry Jo Molina, Frederic Peyrade, Annabelle Mouchotte, Tony Petrella, Emma Proïcs, Bertrand Nadel, Els Verhoeyen, Bruno Taillan, Richard Delarue, Catherine Thieblemont, Laetitia Shintu, Agnès Paquet, Rana Mhaidly, Johanna Chiche, Elodie Villa, Georges Garnier, Pascal Barbry, Josette Brière, Damien Ambrosetti, Nicolas Mounier, André Bosly, Jean-François Michiels, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Université Nice Sophia Antipolis - Faculté de Médecine (UNS UFR Médecine), 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), Centre méditerranéen de médecine moléculaire (C3M), 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 de pharmacologie moléculaire et cellulaire (IPMC), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service d'anatomo-pathologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Pasteur [Nice] (CHU), Hôpital Hôtel Dieu, INSERM U955, équipe 9, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), UNICANCER-Université Côte d'Azur (UCA), Hôpital Princesse Grace [Monaco], Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Cliniques universitaires UCL de Mont-Godinne 5530 Yvoir, Centre de pathologie [Dijon], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Service hématologie Nice, Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'onco-hématologie [AP-HP Hôpital Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Physiopathologie de la survie et de la mort cellulaire et infection virale, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), Centre National de la Recherche Scientifique (CNRS)-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), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de pathologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université Côte d'Azur (UCA), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Antoine Lacassagne, Centre Antoine Lacassagne, Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR50-Université Nice Sophia Antipolis (... - 2019) (UNS), UCL - (MGD) Service d'hématologie, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, and UCL - SSS/IREC/MONT - Pôle Mont Godinne

Subjects
0301 basic medicine, Male, Physiology, Phenformin, Cohort Studies, chemistry.chemical_compound, Mice, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Glyceraldehyde 3-phosphate dehydrogenase, Cells, Cultured, Aged, 80 and over, Predictive marker, biology, GAPDH, Glyceraldehyde-3-Phosphate Dehydrogenases, OxPhos, Middle Aged, glycolysis, Prognosis, 3. Good health, Metformin, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Treatment Outcome, Vincristine, R-CHOP, mTOR, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Lymphoma, Large B-Cell, Diffuse, Rituximab, predictive marker, medicine.drug, Adult, Antimetabolites, Antineoplastic, Mice, Transgenic, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, Young Adult, stomatognathic system, medicine, Animals, Humans, Molecular Biology, Cyclophosphamide, PI3K/AKT/mTOR pathway, B cell, Aged, Retrospective Studies, Glutaminolysis, business.industry, Cell Biology, medicine.disease, L-asparaginase, Mice, Inbred C57BL, 030104 developmental biology, HEK293 Cells, chemistry, Doxorubicin, DLBCL, biology.protein, Cancer research, Prednisone, business, Diffuse large B-cell lymphoma, 030217 neurology & neurosurgery
Abstract

International audience; Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease treated with anti-CD20-based immuno-chemotherapy (R-CHOP). We identified that low levels of GAPDH predict a poor response to R-CHOP treatment. Importantly, we demonstrated that GAPDH(low) lymphomas use OxPhos metabolism and rely on mTORC1 signaling and glutaminolysis. Consistently, disruptors of OxPhos metabolism(phenformin) or glutaminolysis (L-asparaginase) induce cytotoxic responses in GAPDH(low) B cells and improve GAPDH(low) B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDH(high) B cell lymphomas. Ultimately, we selected four GAPDH(low) DLBCL patients, who were refractory to all anti-CD20-based therapies, and targeted DLBCL metabolism-using L-asparaginase (K), mTOR inhibitor (T), and metformin (M) (called KTM therapy). Three out of the four patients presented a complete response upon one cycle of KTM. These findings establish that the GAPDH expression level predicts DLBCL patients' response to R-CHOP treatment and their sensitivity to specific metabolic inhibitors.

Published
2019

5. Regulation of tumor-stroma interactions by the unfolded protein response

Author

Aeid Igbaria, Jozef P. Bossowski, Jean-Ehrland Ricci, Eric Chevet, Camila Rubio-Patiño, Joanna Obacz, 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), 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), University of California [San Francisco] (UC San Francisco), University of California (UC), This work was funded by grants from Institut National du Cancer (INCa, PLBIO: 2017, PLBIO: 2015- 111, INCA_7981), and Ligue Contre le Cancer, EU H2020 MSCA ITN-675448 (TRAINERS) and MSCA RISE-734749 (INSPIRED) to EC, Fondation ARC pour la Recherche sur le Cancer and the Agence Nationale de la Recherche (LABEX SIGNALIFE ANR-11-LABX-0028-01) to JER, Juvenile diabetes research foundation (JDRF 3-PDF-2015-80-A-N) to AI., ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), 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 ), Centre méditérannéen de médecine moléculaire ( C3M ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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), Université Nice Sophia Antipolis (... - 2019) (UNS), University of California [San Francisco] (UCSF), and University of California

Subjects
0301 basic medicine, Stromal cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Endoplasmic Reticulum, Biochemistry, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Immune system, Neoplasms, immunogenic cell death, Animals, Humans, tumor microenvironment, Molecular Biology, Tumor microenvironment, Endoplasmic reticulum, Cell Biology, unfolded protein response, Endoplasmic Reticulum Stress, Cell biology, Crosstalk (biology), 030104 developmental biology, inflammation, 030220 oncology & carcinogenesis, Unfolded protein response, Immunogenic cell death, Protein folding, Stromal Cells, ER stress
Abstract

International audience; The unfolded protein response (UPR) is a conserved adaptive pathway that helps cells cope with the protein misfolding burden within the endoplasmic reticulum (ER). Imbalance between protein folding demand and capacity in the ER leads to a situation called ER stress that is often observed in highly proliferative and secretory tumor cells. As such, activation of the UPR signaling has emerged as a key adaptive mechanism promoting cancer progression. It is becoming widely acknowledged that, in addition to its intrinsic effect on tumor biology, the UPR can also regulate tumor microenvironment. In this review, we discuss how the UPR coordinates the crosstalk between tumor and stromal cells, such as endothelial cells, normal parenchymal cells, and immune cells. In addition, we further describe the involvement of ER stress signaling in the response to current treatments as well as its impact on antitumor immunity mainly driven by immunogenic cell death. Finally, in this context, we discuss the relevance of targeting ER stress/UPR signaling as a potential anticancer approach.

Published
2019

6. Low carbohydrate diet prevents Mcl-1-mediated resistance to BH3-mimetics

Author

Camila Rubio-Patiño, Emma Proïcs, Frédéric Bost, Barbara Zunino, Els Verhoeyen, Jozef P. Bossowski, Elodie Villa, Jean-Ehrland Ricci, Johanna Chiche, and Laura Mondragón

Subjects
0301 basic medicine, Lymphoma, AMP-Activated Protein Kinases, Piperazines, Nitrophenols, Diet, Carbohydrate-Restricted, Mice, AMP-activated protein kinase, hemic and lymphatic diseases, Medicine, Sulfonamides, biology, Biological Mimicry, TOR Serine-Threonine Kinases, 3. Good health, Biphenyl compound, Oncology, Heterografts, Signal transduction, Research Paper, Signal Transduction, medicine.medical_specialty, Programmed cell death, Cell Survival, low carbohydrate diet, EEF2, 03 medical and health sciences, Internal medicine, Cell Line, Tumor, Proto-Oncogene Proteins, cancer, Animals, Humans, PI3K/AKT/mTOR pathway, business.industry, Biphenyl Compounds, AMPK, Mcl-1, Peptide Fragments, Elongation factor, Disease Models, Animal, 030104 developmental biology, Endocrinology, Drug Resistance, Neoplasm, Protein Biosynthesis, Immunology, biology.protein, Myeloid Cell Leukemia Sequence 1 Protein, business, metabolism, resistance to treatment
Abstract

// Camila Rubio-Patino 1, 2 , Jozef P. Bossowski 1, 2 , Elodie Villa 1, 2 , Laura Mondragon 1, 2 , Barbara Zunino 1, 2 , Emma Proics 1, 2, 3 , Johanna Chiche 1, 2 , Frederic Bost 2, 4 , Els Verhoeyen 1, 2 , Jean-Ehrland Ricci 1, 2 1 Inserm, U1065, Centre Mediterraneen de Medecine Moleculaire (C3M), Equipe “Controle Metabolique des Morts Cellulaires”, Nice, France 2 Universite Nice Cote d’Azur, Inserm, C3M, France 3 Centre Hospitalier Universitaire de Nice, Departement d’Anesthesie Reanimation, Nice, France 4 Inserm, U1065, Centre Mediterraneen de Medecine Moleculaire (C3M), Equipe “Cellular and Molecular Physiopathology of Obesity and Diabetes”, Nice, France Correspondence to: Jean-Ehrland Ricci, email: ricci@unice.fr Keywords: metabolism, cancer, resistance to treatment, Mcl-1, low carbohydrate diet Received: May 27, 2016 Accepted: September 19, 2016 Published: September 28, 2016 ABSTRACT Overexpression of Mcl-1 is implicated in resistance of several cancers to chemotherapeutic treatment, therefore identifying a safe way to decrease its expression in tumor cells represents a central goal. We investigated if a modulation of the diet could impact on Mcl-1 expression using a Myc-driven lymphoma model. We established that a partial reduction of caloric intake by 25% represents an efficient way to decrease Mcl-1 expression in tumor cells. Furthermore, using isocaloric custom diets, we observed that carbohydrates (CHO) are the main regulators of Mcl-1 expression within the food. Indeed, feeding lymphoma-bearing mice with a diet having 25% less carbohydrates was sufficient to decrease Mcl-1 expression by 50% in lymphoma cells. We showed that a low CHO diet resulted in AMPK activation and mTOR inhibition leading to eukaryotic elongation factor 2 (eEF2) inhibition, blocking protein translation elongation. Strikingly, a low CHO diet was sufficient to sensitize Myc-driven lymphoma-bearing mice to ABT-737-induced cell death in vivo . Thus reducing carbohydrate intake may represent a safe way to decrease Mcl-1 expression and to sensitize tumor cells to anti-cancer therapeutics.

Published
2016

7. Reshaping the Immune Tumor Microenvironment Through IRE1 Signaling

Author

Camila Rubio-Patiño, Jozef P. Bossowski, Eric Chevet, Jean-Ehrland Ricci, 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), 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), RISE-734749, MSCA, Multiple Sclerosis Center of Atlanta, ITN-675448, MSCA, Multiple Sclerosis Center of Atlanta, ANR-11-LABX-0028-01, Labex, ANR, Agence Nationale de la Recherche, ARC, Australian Research Council, ARC, Fondation ARC pour la Recherche sur le Cancer, MSCA, H2020 Marie Skłodowska-Curie Actions, PLBIO2017, INCa, Institut National Du Cancer, ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), 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), 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, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Protein Serine-Threonine Kinases, immune response, 03 medical and health sciences, stress, Immune system, medicine, Tumor Microenvironment, Animals, Humans, cancer, Molecular Biology, Secretory pathway, Tumor microenvironment, Endoplasmic reticulum, Cancer, medicine.disease, Cell biology, endoplasmic reticulum, 030104 developmental biology, nutrition, Unfolded protein response, Unfolded Protein Response, Molecular Medicine, Intracellular, Signal Transduction
Abstract

International audience; The ability of a tumor cell to cope with environmental and intracellular stress depends on its capacity to activate appropriate adaptive pathways. As such, the endoplasmic reticulum (ER) adjusts the adaptive capacity of tumor cells by engaging the unfolded protein response (UPR). The UPR maintains the functionality of the secretory pathway, thereby allowing tumor cells to shape their microenvironment, thus likely determining the nature of the tumor immune response. Consequently, this makes the UPR very relevant in the context of cancer therapeutics. We focus here on inositol-requiring enzyme 1α (IRE1) and compile novel molecular mechanisms demonstrating that tumoral UPR controls the tumor microenvironment (TME) and the immune response, therefore opening potential novel therapeutic avenues. © 2018 Elsevier Ltd

Published
2018

8. GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism

Author

Laura Mondragón, Philippe Gaulard, Jaap G Neels, Camila Rubio-Patiño, Frédéric Coutant, Laurent Boyer, François Lemonnier, Florian Muller, Elodie Villa, Rana Mhaidly, Vahid Asnafi, Thierry Passeron, Gian Marco De Donatis, Jean-François Peyron, Nicole Fabien, Els Verhoeyen, Sandrine Marchetti, Pascal Dao, Laura Sormani, Marie Jacquin, Marie Tosolini, Jean-Ehrland Ricci, Emma Proïcs, Anne Doye, Laurent Genestier, Jozef P. Bossowski, Anthony Martin, Véronique Imbert, Frederic Luciano, Jean-Jacques Fournié, Rachid Benhida, Caroline Pons, Johanna Chiche, 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), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Nice (ICN), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Hospices Civils de Lyon (HCL), Centre méditérannéen de médecine moléculaire (C3M), 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), 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), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Physiopathologie de la survie et de la mort cellulaire et infection virale, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM), CCSD, Accord Elsevier, Université Nice Sophia Antipolis (... - 2019) (UNS), Université Nice Sophia Antipolis (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Immunogenomique et Inflammation, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (CRCL), Centre de Recherche en Cancérologie de Toulouse (CRCT), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (Equipe EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université Côte d'Azur (UCA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-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)-IFR50-Université Nice Sophia Antipolis (... - 2019) (UNS), and Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)

Subjects
0301 basic medicine, Male, Cancer Research, [SDV]Life Sciences [q-bio], T-Lymphocytes, Datasets as Topic, chemistry.chemical_compound, 0302 clinical medicine, Glyceraldehyde 3-phosphate dehydrogenase, ComputingMilieux_MISCELLANEOUS, biology, NF-kappa B, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, Female, Signal Transduction, Genetically modified mouse, Angioimmunoblastic T-cell lymphoma, Lineage (genetic), T cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, Transgenic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Protein Serine-Threonine Kinases, Lymphoma, T-Cell, 03 medical and health sciences, stomatognathic system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, Animals, Humans, Cell Lineage, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Protein Kinase Inhibitors, Aged, NF-κB, medicine.disease, Lymphoma, Disease Models, Animal, 030104 developmental biology, HEK293 Cells, chemistry, Immunoblastic Lymphadenopathy, biology.protein, Cancer research, Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating), Function (biology)
Abstract

GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.

Published
2018

9. 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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