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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, 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), Equipe Labellisée LIGUE Contre le Cancer [Nice] (EL/LCC), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), la Ligue Nationale Contre le Cancer 'Equipe Labellisée, 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), and Ricci, Jean-Ehrland

Subjects
X-Box Binding Protein 1, [SDV]Life Sciences [q-bio], Immunology, Immunity, apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, IRE1α, UPR, Protein Serine-Threonine Kinases, [SDV] Life Sciences [q-bio], Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, Neoplasms, Endoribonucleases, Animals, Immunology and Allergy, RIDD, anti-cancer immunosurveillance, XBP1s, Neoplastic Processes, Signal Transduction, Cancer
Abstract

International audience; 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 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

2. Tumoral microenvironment prevents de novo asparagine biosynthesis in B cell lymphoma, regardless of ASNS expression

Author

Manuel Grima-Reyes, Ashaina Vandenberghe, Ivan Nemazanyy, Pauline Meola, Rachel Paul, Julie Reverso-Meinietti, Adriana Martinez-Turtos, Nicolas Nottet, Wai-Kin Chan, Philip L. Lorenzi, Sandrine Marchetti, Jean-Ehrland Ricci, 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), Equipe Labellisée LIGUE Contre le Cancer [Nice] (EL/LCC), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The University of Texas M.D. Anderson Cancer Center [Houston], and Ricci, Jean-Ehrland

Subjects
Multidisciplinary, Lymphoma, B-Cell, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Aspartate-Ammonia Ligase, Precursor Cell Lymphoblastic Leukemia-Lymphoma, [SDV] Life Sciences [q-bio], Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glutaminase, Cell Line, Tumor, Tumor Microenvironment, Animals, Asparaginase, Asparagine
Abstract

Depletion of circulating asparagine with l -asparaginase (ASNase) is a mainstay of leukemia treatment and is under investigation in many cancers. Expression levels of asparagine synthetase (ASNS), which catalyzes asparagine synthesis, were considered predictive of cancer cell sensitivity to ASNase treatment, a notion recently challenged. Using [U- 13 C 5 ]- l -glutamine in vitro and in vivo in a mouse model of B cell lymphomas (BCLs), we demonstrated that supraphysiological or physiological concentrations of asparagine prevent de novo asparagine biosynthesis, regardless of ASNS expression levels. Overexpressing ASNS in ASNase-sensitive BCL was insufficient to confer resistance to ASNase treatment in vivo. Moreover, we showed that ASNase’s glutaminase activity enables its maximal anticancer effect. Together, our results indicate that baseline ASNS expression (low or high) cannot dictate BCL dependence on de novo asparagine biosynthesis and predict BCL sensitivity to dual ASNase activity. Thus, except for ASNS-deficient cancer cells, ASNase’s glutaminase activity should be considered in the clinic.

Published
2022

3. No Parkin Zone: Mitophagy without Parkin

Author

Sandrine Marchetti, Elodie Villa, and Jean-Ehrland Ricci

Subjects
0301 basic medicine, Ubiquitin-Protein Ligases, Mitophagy, Regulator, PINK1, Cell Biology, Biology, Mitochondrion, Parkin, Mitochondria, Mitochondrial autophagy, Cell biology, 03 medical and health sciences, 030104 developmental biology, Animals, Humans
Abstract

Mitochondria are essential highly dynamic organelles that provide the necessary energy for a variety of different processes, such as survival, proliferation, and migration. In order to maintain an intact mitochondrial network, cells have developed quality control systems that allow the removal of damaged or superfluous mitochondria by selective mitochondrial autophagy called mitophagy. Although the parkin/PINK1 axis is often considered the main regulator of mitophagy, a growing body of evidence has shown that this pathway is not unique and that mitophagy can still be functional in the absence of parkin. Here, we will review recent literature describing parkin-independent mitophagy and its role in various physiopathological conditions, therefore representing potential new targets to treat diseases affected by dysregulated mitophagy.

Published
2018

4. Escherichia coli Rho GTPase-activating toxin CNF1 mediates NLRP3 inflammasome activation via p21-activated kinases-1/2 during bacteraemia in mice

Author

Alexandre Gallerand, Arnaud Jacquel, Pedro Henrique Viana Saavedra, Cedric Torre, Paul Chaintreuil, Sandrine Marchetti, Alissa Majoor, Mohamed Lamkanfi, Raymond Ruimy, Céline Loubatier, Amaury Rey, Anne Doye, Laurent Boyer, Benedicte F. Py, Grégory Michel, Johan Courjon, Rodolphe Guinamard, Patrick Munro, Dorota Czerucka, Orane Visvikis, Océane Dufies, Els Verhoeyen, 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 Hospitalier Universitaire de Nice (CHU Nice), Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University [Belgium] (UGENT), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre Scientifique de Monaco (CSM), Laboratoire International Associé Réponse des Organismes et Populations face au Stress Environnemental - Université Côte d’Azur - Centre Scientifique de Monaco (LIA ROPSE), Université Côte d’Azur - Centre Scientifique de Monaco, Université Nice Sophia Antipolis (1965 - 2019) (UNS), Universiteit Gent = Ghent University (UGENT), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE15-0001,AVI,Identification de l'inflammasome impliqué dans l'Immunité Anti-Virulence: Impact sur notre façon de combattre la bactériémie(2017), 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), and Guinamard, Rodolphe

Subjects
Microbiology (medical), Inflammasomes, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, Bacterial Toxins, Bacteremia, GTPase, Applied Microbiology and Biotechnology, Microbiology, Article, 03 medical and health sciences, Mice, PAK1, NLR Family, Pyrin Domain-Containing 3 Protein, Genetics, medicine, Escherichia coli, Animals, Phosphorylation, p21-activated kinases, Escherichia coli Infections, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, integumentary system, 030306 microbiology, Chemistry, Kinase, Escherichia coli Proteins, Pyroptosis, Pattern recognition receptor, Inflammasome, Cell Biology, Bacterial Load, Immunity, Innate, 3. Good health, Cell biology, rac GTP-Binding Proteins, [SDV] Life Sciences [q-bio], Cytokine, p21-Activated Kinases, medicine.drug, Signal Transduction
Abstract

Inflammasomes are signalling platforms that are assembled in response to infection or sterile inflammation by cytosolic pattern recognition receptors. The consequent inflammasome-triggered caspase-1 activation is critical for the host defence against pathogens. During infection, NLRP3, which is a pattern recognition receptor that is also known as cryopyrin, triggers the assembly of the inflammasome-activating caspase-1 through the recruitment of ASC and Nek7. The activation of the NLRP3 inflammasome is tightly controlled both transcriptionally and post-translationally. Despite the importance of the NLRP3 inflammasome regulation in autoinflammatory and infectious diseases, little is known about the mechanism controlling the activation of NLRP3 and the upstream signalling that regulates the NLRP3 inflammasome assembly. We have previously shown that the Rho-GTPase-activating toxin from Escherichia coli cytotoxic necrotizing factor-1 (CNF1) activates caspase-1, but the upstream mechanism is unclear. Here, we provide evidence of the role of the NLRP3 inflammasome in sensing the activity of bacterial toxins and virulence factors that activate host Rho GTPases. We demonstrate that this activation relies on the monitoring of the toxin’s activity on the Rho GTPase Rac2. We also show that the NLRP3 inflammasome is activated by a signalling cascade that involves the p21-activated kinases 1 and 2 (Pak1/2) and the Pak1-mediated phosphorylation of Thr 659 of NLRP3, which is necessary for the NLRP3–Nek7 interaction, inflammasome activation and IL-1β cytokine maturation. Furthermore, inhibition of the Pak–NLRP3 axis decreases the bacterial clearance of CNF1-expressing UTI89 E. coli during bacteraemia in mice. Taken together, our results establish that Pak1 and Pak2 are critical regulators of the NLRP3 inflammasome and reveal the role of the Pak–NLRP3 signalling axis in vivo during bacteraemia in mice. Here, the authors present the upstream pathway that controls the activation of the NLRP3 inflammasome during bacteraemia. The CNF1 toxin from Escherichia coli activates the Rho GTPase Rac2 and its activity is sensed by NLRP3, which is activated by a signalling cascade involving p21-activated kinases 1 and 2.

Published
2021

5. Pharmacological preconditioning protects from ischemia/reperfusion-induced apoptosis by modulating Bcl-xL expression through a ROS-dependent mechanism

Author

Johanna Chiche, Jean-Ehrland Ricci, Romain M. Rozier, Blandine Madji Hounoum, Elodie Villa, Rachel Paul, Els Verhoeyen, Sandrine Marchetti, Ashaina Vandenberghe, Rana Mhaidly, Michel Carles, and Marc Raucoules

Subjects
0301 basic medicine, Programmed cell death, Cell Survival, Ischemia, bcl-X Protein, Bcl-xL, Apoptosis, Myocardial Reperfusion Injury, Pharmacology, Biochemistry, 03 medical and health sciences, Sevoflurane, 0302 clinical medicine, medicine, Animals, Humans, Hypoglycemic Agents, Myocytes, Cardiac, Induced pluripotent stem cell, Molecular Biology, Protein kinase B, chemistry.chemical_classification, Reactive oxygen species, biology, Cell Biology, medicine.disease, Metformin, Rats, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Reperfusion Injury, biology.protein, Signal transduction, Reactive Oxygen Species, Signal Transduction
Abstract

Myocardial ischemia/reperfusion (I/R) injury is a frequent perioperative threat, with numerous strategies developed to limit and/or prevent it. One interesting axis of research is the anesthetic preconditioning (APc) agent's hypothesis (such as sevoflurane, SEV). However, APc's mode of action is still poorly understood and volatile anesthetics used as preconditioning agents are often not well suited in clinical practice. Here, in vitro using H9C2 cells lines (in myeloblast state or differentiated toward cardiomyocytes) and in vivo in mice, we identified that SEV-induced APc is mediated by a mild induction of reactive oxygen species (ROS) that activates Akt and induces the expression of the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-xL), therefore protecting cardiomyocytes from I/R-induced death. Furthermore, we extended these results to human cardiomyocytes (derived from induced pluripotent stem - IPS - cells). Importantly, we demonstrated that this protective signaling pathway induced by SEV could be stimulated using the antidiabetic agent metformin (MET), suggesting the preconditioning properties of MET. Altogether, our study identified a signaling pathway allowing APc of cardiac injuries as well as a rational for the use of MET as a pharmacological preconditioning agent to prevent I/R injuries.

Published
2020

6. 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

7. 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

8. Differentiation inducing factor 3 mediates its anti-leukemic effect through ROS-dependent DRP1-mediated mitochondrial fission and induction of caspase-independent cell death

Author

Alix Dubois, Arnaud Jacquel, Sandrine Marchetti, Clemence Ginet, Frederic Luciano, Nathan Furstoss, Thomas Cluzeau, Guillaume Robert, Mohamed Amine Hamouda, Mohsine Driowya, Rachid Benhida, Patrick Auberger, Jean-Ehrland Ricci, Wedjene El Manaa, and Amine Belaid

Subjects
Dynamins, 0301 basic medicine, autophagy, Programmed cell death, Cellular differentiation, Mice, Nude, Apoptosis, Mitochondrion, Mitochondrial Dynamics, GTP Phosphohydrolases, Mitochondrial Proteins, DIF-3, Mice, 03 medical and health sciences, Biomarkers, Tumor, Animals, Humans, Phosphorylation, Caspase, Cell Proliferation, Leukemia, mitochondria fission, biology, Gene Expression Regulation, Leukemic, Cell growth, fungi, Cell Differentiation, Xenograft Model Antitumor Assays, humanities, Differentiation-inducing factor, Mitochondria, Cell biology, Hexanones, cell death, 030104 developmental biology, Oncology, Caspases, biology.protein, Female, Mitochondrial fission, K562 Cells, Reactive Oxygen Species, Microtubule-Associated Proteins, Research Paper
Abstract

Differentiation-inducing factor (DIF) defines a group of chlorinated hexaphenones that orchestrate stalk-cell differentiation in the slime mold Dictyostelium discoideum (DD). DIF-1 and 3 have also been reported to have tumor inhibiting properties; however, the mechanisms that underlie the effects of these compounds remain poorly defined. Herein, we show that DIF-3 rapidly triggers Ca2+ release and a loss of mitochondrial membrane potential (MMP) in the absence of cytochrome c and Smac release and without caspase activation. Consistently with these findings, we also detected no evidence of apoptosis in cells treated with DIF-3 but instead found that this compound induced autophagy. In addition, DIF-3 promoted mitochondrial fission in K562 and HeLa cells, as assessed by electron and confocal microscopy analysis. Importantly, DIF-3 mediated the phosphorylation and redistribution of dynamin-related protein 1 (DRP1) from the cytoplasmic to the microsomal fraction of K562 cells. Pharmacological inhibition or siRNA silencing of DRP1 not only inhibited mitochondrial fission but also protected K562 cells from DIF-3-mediated cell death. Furthermore, DIF-3 potently inhibited the growth of imatinib-sensitive and imatinib-resistant K562 cells. It also inhibited tumor formation in athymic mice engrafted with an imatinib-resistant CML cell line. Finally, DIF-3 exhibited a clear selectivity toward CD34+ leukemic cells from CML patients, compared with CD34− cells. In conclusion, we show that the potent anti-leukemic effect of DIF-3 is mediated through the induction of mitochondrial fission and caspase-independent cell death. Our findings may have important therapeutic implications, especially in the treatment of tumors that exhibit defects in apoptosis regulation.

Published
2016

9. BCL-B (BCL2L10) is overexpressed in patients suffering from multiple myeloma (MM) and drives an MM-like disease in transgenic mice

Author

Nathalie Rochet, Arnaud Jacquel, Martine Amiot, Alix Dubois, Jean-Michel Karsenti, Patricia Gomez-Bougie, Aude Mallavialle, Thomas Cluzeau, Alexandre Puissant, Pierre-Yves Jeandel, Pascal Colosetti, Jean-Gabriel Fuzibet, Bertrand Nadel, Sandrine Marchetti, Patrick Auberger, Hervé Avet-Loiseau, Nina Fenouille, Romeo Cassel, Marcel Deckert, Jerome Gilleron, Frederic Luciano, Valentine Richez, Beatrice Bailly-Maitre, Sandrine Roulland, Kenneth C. Anderson, Paul Hofman, Mohamed-Amine Hamouda, Guillaume Robert, Emmanuel Griessinger, Claudine Blin-Wakkach, Diogo Gonçalvès, 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), Ligue Nationale Contre le Cancer (LNCC), Dana-Farber Cancer Institute [Boston], Boston Children's Hospital, Centre Hospitalier Universitaire de Nice, Centre Hospitalier Universitaire de Nice (CHU Nice), Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), 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), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Biologie Valrose (IBV), 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 National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Pathologie Clinique et Expérimentale, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Hôpital pasteur [Colmar]-Centre Hospitalier Universitaire de Nice (CHU Nice), Laboratoire de PhysioMédecine Moléculaire (LP2M), 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), Département Universitaire Nice, Hôpital de Nice, This work was supported by the Ligue Nationale Contre le Cancer (Equipe Label-lisée grant R08001AA), the Fondation de France (grant R08080AA), and an ARC Foun-dation program (grant PGA120140200777) and an ARC project (2015–2016). This work was also funded by the French government (French National Research Agency, ANR) through the 'Investments for the future' LABEX SIGNALIFE: program reference #ANR-11-LABX-0028-01., ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), 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 / Nantes - Angers (CRCNA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Hôpital pasteur [Colmar]-Centre Hospitalier Universitaire de Nice (CHU Nice), Laboratoire de PhysioMédecine Moléculaire (LP2M), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), ANR: 11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), 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), Koch Institute for Integrative Cancer Research at MIT [Cambridge, MA], 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), Bernardo, Elizabeth, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, 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), Koch Institute for Integrative Cancer Research at MIT, and Fenouille, Nina

Subjects
0301 basic medicine, Melphalan, Pathology, medicine.medical_specialty, Immunology, bcl-X Protein, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, Transgenic, Article, Malignant transformation, Pathogenesis, 03 medical and health sciences, Mice, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, Cell Line, Tumor, Hypergammaglobulinemia, medicine, Immunology and Allergy, Animals, Humans, Multiple myeloma, Research Articles, Cell Proliferation, Bortezomib, business.industry, Plasmacytosis, Cell Differentiation, medicine.disease, 3. Good health, Mice, Inbred C57BL, 030104 developmental biology, Proto-Oncogene Proteins c-bcl-2, 030220 oncology & carcinogenesis, Syndecan-1, business, Multiple Myeloma, Monoclonal gammopathy of undetermined significance, medicine.drug
Abstract

Multiple myeloma (MM) evolves from a premalignant condition known as monoclonal gammopathy of undetermined significance (MGUS). However, the factors underlying the malignant transformation of plasmocytes in MM are not fully characterized. We report here that Eµ-directed expression of the antiapoptotic Bcl-B protein in mice drives an MM phenotype that reproduces accurately the human disease. Indeed, with age, Eµ-bcl-b transgenic mice develop the characteristic features of human MM, including bone malignant plasma cell infiltration, a monoclonal immunoglobulin peak, immunoglobulin deposit in renal tubules, and highly characteristic bone lytic lesions. In addition, the tumors are serially transplantable in irradiated wild-type mice, underlying the tumoral origin of the disease. Eµ-bcl-b plasmocytes show increased expression of a panel of genes known to be dysregulated in human MM pathogenesis. Treatment of Eµ-bcl-b mice with drugs currently used to treat patients such as melphalan and VELCADE efficiently kills malignant plasmocytes in vivo. Finally, we find that Bcl-B is overexpressed in plasmocytes from MM patients but neither in MGUS patients nor in healthy individuals, suggesting that Bcl-B may drive MM. These findings suggest that Bcl-B could be an important factor in MM disease and pinpoint Eµ-bcl-b mice as a pertinent model to validate new therapies in MM., Ligue nationale contre le cancer (France) (Equipe Labellisée Grant R08001AA), Fondation de France (Grant R08080AA), Fondation ARC pour la Recherche sur le Cancer (Grant PGA120140200777), Fondation ARC pour la Recherche sur le Cancer (Project 2015–2016), French Research National Agency (Grant ANR-11-LABX-0028-01)

Published
2016

10. Bax inhibitor-1 protects from nonalcoholic steatohepatitis by limiting inositol-requiring enzyme 1 alpha signaling in mice

Author

Rodolphe Anty, Guido Kroemer, Cynthia Lebeaupin, Philippe Gual, Gilbert Adam, Albert Tran, Carmelo Luci, Stéphanie Patouraux, Déborah Rousseau, Frederic Luciano, Antonio Iannelli, Sandra Lacas-Gervais, Sandrine Marchetti, Déborah Vallée, Stéphanie Bonnafous, Béatrice Bailly-Maitre, CCMA - Centre Commun de Microscopie Appliquée, and Université Nice Côte D'Azur

Subjects
0301 basic medicine, Male, medicine.medical_specialty, XBP1, Inflammasomes, [SDV]Life Sciences [q-bio], Endoribonuclease, Immunoblotting, Cell Culture Techniques, Aspartate transaminase, Protein Serine-Threonine Kinases, Real-Time Polymerase Chain Reaction, 03 medical and health sciences, Mice, Non-alcoholic Fatty Liver Disease, Internal medicine, Nonalcoholic fatty liver disease, Endoribonucleases, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Animals, Humans, ComputingMilieux_MISCELLANEOUS, Hepatology, biology, Cell Death, Chemistry, Membrane Proteins, Inflammasome, medicine.disease, Endoplasmic Reticulum Stress, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Alanine transaminase, Liver, Unfolded protein response, biology.protein, Cytokines, Steatohepatitis, Apoptosis Regulatory Proteins, medicine.drug, Signal Transduction
Abstract

Endoplasmic reticulum (ER) stress is activated in nonalcoholic fatty liver disease (NAFLD), raising the possibility that ER stress-dependent metabolic dysfunction, inflammation, and cell death underlie the transition from steatosis to steatohepatitis (nonalcoholic steatohepatitis; NASH). B-cell lymphoma 2 (BCL2)-associated X protein (Bax) inhibitor-1 (BI-1), a negative regulator of the ER stress sensor, inositol-requiring enzyme 1 alpha (IRE1α), has yet to be explored in NAFLD as a hepatoprotective agent. We hypothesized that the genetic ablation of BI-1 would render the liver vulnerable to NASH because of unrestrained IRE1α signaling. ER stress was induced in wild-type and BI-1-/- mice acutely by tunicamycin (TM) injection (1 mg/kg) or chronically by high-fat diet (HFD) feeding to determine NAFLD phenotype. Livers of TM-treated BI-1-/- mice showed IRE1α-dependent NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation, hepatocyte death, fibrosis, and dysregulated lipid homeostasis that led to liver failure within a week. The analysis of human NAFLD liver biopsies revealed BI-1 down-regulation parallel to the up-regulation of IRE1α endoribonuclease (RNase) signaling. In HFD-fed BI-1-/- mice that presented NASH and type 2 diabetes, exaggerated hepatic IRE1α, X-box binding protein 1 (XBP1), and C/EBP homologous protein (CHOP) expression was linked to activated NLRP3 inflammasome and caspase-1/-11. Rises in interleukin (IL)-1β, IL-6, monocyte chemoattractant protein 1 (MCP1), chemokine (C-X-C motif) ligand 1 (CXCL1), and alanine transaminase (ALT)/aspartate transaminase (AST) levels revealed significant inflammation and injury, respectively. Pharmacological inhibition of IRE1α RNase activity with the small molecules, STF-083010 or 4μ8c, was evaluated in HFD-induced NAFLD. In BI-1-/- mice, either treatment effectively counteracted IRE1α RNase activity, improving glucose tolerance and rescuing from NASH. The hepatocyte-specific role of IRE1α RNase activity in mediating NLRP3 inflammasome activation and cell death was confirmed in primary mouse hepatocytes by IRE1α axis knockdown or its inhibition with STF-083010 or 4μ8c. Conclusion Targeting IRE1α-dependent NLRP3 inflammasome signaling with pharmacological agents or by BI-1 may represent a tangible therapeutic strategy for NASH. (Hepatology 2018).

Published
2018

11. 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

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

Author

Pascal Colosetti, Emma Proïcs, Frederic Luciano, Jean-Ehrland Ricci, Guillaume Robert, Lazaro Emilio Aira, Fabien Gautier, Laurie Signetti, Sandrine Marchetti, Philippe Juin, Parvati Gamas, Elodie Villa, Sandrine Obba, Béatrice Bailly-Maitre, Arnaud Jacquel, Patrick Auberger, Stress Adaptation and Tumor Escape in breast cancer - SATE ( CRCINA - Département ONCO - Equipe 8 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Bernardo, Elizabeth, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
0301 basic medicine, Cancer Research, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, environment and public health, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, LYN, hemic and lymphatic diseases, Genetics, Animals, Humans, Tyrosine, Molecular Biology, Cells, Cultured, Bcl-2-Like Protein 11, biology, Cytochrome c, Tyrosine phosphorylation, hemic and immune systems, Oncogenes, Mitochondria, Cell biology, enzymes and coenzymes (carbohydrates), Cell Transformation, Neoplastic, HEK293 Cells, src-Family Kinases, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, Phosphorylation, biological phenomena, cell phenomena, and immunity, K562 Cells, Tyrosine kinase, HeLa Cells, Signal Transduction
Abstract

International audience; Phosphorylation of Ser/Thr residues is a well-established modulating mechanism of the pro-apoptotic function of the BH3-only protein Bim. However, nothing is known about the putative tyrosine of this Bcl-2 family member and its potential impact on Bim function and subsequent Bax/Bak-mediated cytochrome c release and apoptosis. As we have previously shown that the tyrosine kinase Lyn could behave as an anti-apoptic molecule, we investigated whether this Src family member could directly regulate the pro-apoptotic function of Bim. In the present study, we show that Bim is phosphorylated onto tyrosine residues 92 and 161 by Lin, which results is an inhibition of its pro-apoptotic function. Mechanistically, we show that Lyn-dependent tyrosine phosphorylation of Bim increases its interaction with anti-apoptic members such as Bcl-xL, therefore limiting mitochondrial outer membrane permeabilization and subsequent apoptosis. Collectively, our data uncover one molecular mechanism through which the oncogenic tyrosine kinase Lyn negatively regulates the mitochondrial apoptic pathway, which may contribute to the transformation and/or the chemotherapeutic resistance of cancer cells.

Published
2018

13. Lysosomal Cholesterol Hydrolysis Couples Efferocytosis to Anti-Inflammatory Oxysterol Production

Author

Isabelle Dugail, Nemanja Vujic, Paul Dasilva-Jardine, Andrea E. Bochem, Kees Hovingh, Emmanuel L. Gautier, Fabienne Foufelle, Thibault Barouillet, François Orange, Madalina Duta-Mare, Manon Viaud, Laurent Yvan-Charvet, Lazaro Emilio Aira, Laurent Boyer, Christian Stehlik, Sandrine Marchetti, Edward B. Thorp, Stoyan Ivanov, Elsa Garcia, Dagmar Kratky, Rodolphe Guinamard, Isabelle Hainault, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), and 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)

Subjects
0301 basic medicine, rac1 GTP-Binding Protein, Erythrocytes, Oxysterol, Physiology, Inflammasomes, [SDV]Life Sciences [q-bio], Hypercholesterolemia, Inflammation, Apoptosis, Mitochondrion, Article, Apoptotic cell clearance, 03 medical and health sciences, Mice, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Macrophage, Animals, Lymphocytes, Efferocytosis, ComputingMilieux_MISCELLANEOUS, Caspase, Liver X Receptors, biology, Chemistry, Hydrolysis, Macrophages, Neuropeptides, Biological Transport, Oxysterols, Sterol Esterase, Cell biology, Mitochondria, Mice, Inbred C57BL, 030104 developmental biology, Cholesterol, Receptors, LDL, Splenomegaly, biology.protein, Cholesterol Esters, medicine.symptom, Cardiology and Cardiovascular Medicine, Lysosomes
Abstract

Rationale: Macrophages face a substantial amount of cholesterol after the ingestion of apoptotic cells, and the LIPA (lysosomal acid lipase) has a major role in hydrolyzing cholesteryl esters in the endocytic compartment. Objective: Here, we directly investigated the role of LIPA-mediated clearance of apoptotic cells both in vitro and in vivo. Methods and Results: We show that LIPA inhibition causes a defective efferocytic response because of impaired generation of 25-hydroxycholesterol and 27-hydroxycholesterol. Reduced synthesis of 25-hydroxycholesterol after LIPA inhibition contributed to defective mitochondria-associated membrane leading to mitochondrial oxidative stress–induced NLRP3 (NOD-like receptor family, pyrin domain containing) inflammasome activation and caspase-1–dependent Rac1 (Ras-related C3 botulinum toxin substrate 1) degradation. A secondary event consisting of failure to appropriately activate liver X receptor–mediated pathways led to mitigation of cholesterol efflux and apoptotic cell clearance. In mice, LIPA inhibition caused defective clearance of apoptotic lymphocytes and stressed erythrocytes by hepatic and splenic macrophages, culminating in splenomegaly and splenic iron accumulation under hypercholesterolemia. Conclusions: Our findings position lysosomal cholesterol hydrolysis as a critical process that prevents metabolic inflammation by enabling efficient macrophage apoptotic cell clearance.

Published
2018

14. 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

15. NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

Author

Peter Vandenabeele, Sandrine Marchetti, Jorge Caamano, F. Mair, Jacques Piette, Caroline Remouchamps, Cécile Bénézech, Layla Boutaffala, Mathias Heikenwalder, Mathieu J.M. Bertrand, Florian Reisinger, Jean-Ehrland Ricci, A. Hupalowska, Gitta Maria Seleznik, Marianne K. Janas, M. T. Fernandes, Emmanuel Dejardin, Corinne Ganeff, Burkhard Becher, and Percy A. Knolle

Subjects
Programmed cell death, Fas-Associated Death Domain Protein, Apoptosis, Thymus Gland, Protein Serine-Threonine Kinases, Cell Line, Inhibitor of Apoptosis Proteins, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Lymphotoxin beta Receptor, Animals, Humans, FADD, Phosphorylation, Molecular Biology, 030304 developmental biology, Mice, Knockout, Caspase 8, Original Paper, 0303 health sciences, biology, Tumor Necrosis Factor-alpha, Kinase, GTPase-Activating Proteins, HEK 293 cells, NF-kappa B, NF-κB, Cell Biology, Cell biology, Mice, Inbred C57BL, HEK293 Cells, Liver, chemistry, Receptors, Tumor Necrosis Factor, Type I, 030220 oncology & carcinogenesis, biology.protein, Tumor necrosis factor alpha, Signal Transduction
Abstract

NF-κB-inducing kinase (NIK) is well-known for its role in promoting p100/NF-κB2 processing into p52, a process defined as the alternative, or non-canonical, NF-κB pathway. Here we reveal an unexpected new role of NIK in TNFR1-mediated RIP1-dependent apoptosis, a consequence of TNFR1 activation observed in c-IAP1/2-depleted conditions. We show that NIK stabilization, obtained by activation of the non-death TNFRs Fn14 or LTβR, is required for TNFα-mediated apoptosis. These apoptotic stimuli trigger the depletion of c-IAP1/2, the phosphorylation of RIP1 and the RIP1 kinase-dependent assembly of the RIP1/FADD/caspase-8 complex. In the absence of NIK, the phosphorylation of RIP1 and the formation of RIP1/FADD/caspase-8 complex are compromised while c-IAP1/2 depletion is unaffected. In vitro kinase assays revealed that recombinant RIP1 is a bona fide substrate of NIK. In vivo, we demonstrated the requirement of NIK pro-death function, but not the processing of its substrate p100 into p52, in a mouse model of TNFR1/LTβR-induced thymus involution. In addition, we also highlight a role for NIK in hepatocyte apoptosis in a mouse model of virus-induced TNFR1/RIP1-dependent liver damage. We conclude that NIK not only contributes to lymphoid organogenesis, inflammation and cell survival but also to TNFR1/RIP1-dependent cell death independently of the alternative NF-κB pathway.

Published
2015

16. GAPDH enhances the aggressiveness and the vascularization of non-Hodgkin’s B lymphomas via NF-κB-dependent induction of HIF-1α

Author

Josette Brière, Diogo Gonçalvès, M Guyot, Nicolas Mounier, A Mouchotte, Marie Bénéteau, Véronique Imbert, Catherine Thieblemont, Ophélie Meynet, Johanna Chiche, Sandrine Marchetti, Laura Mondragón, S Pommier, Michel Carles, J-E Ricci, Pascal Colosetti, Barbara Zunino, E Verhoeyen, and Gilles Pagès

Subjects
Vascular Endothelial Growth Factor A, Cancer Research, TRAF2, Lymphoma, Biopsy, Mice, Transgenic, Gene Expression Regulation, Enzymologic, Proto-Oncogene Proteins c-myc, Mice, chemistry.chemical_compound, stomatognathic system, Cell Line, Tumor, medicine, Animals, Humans, Enzyme Inhibitors, Glyceraldehyde 3-phosphate dehydrogenase, Regulation of gene expression, biology, Lymphoma, Non-Hodgkin, NF-kappa B p50 Subunit, NF-κB, Hematology, Hypoxia-Inducible Factor 1, alpha Subunit, TNF Receptor-Associated Factor 2, medicine.disease, Molecular biology, Gene Expression Regulation, Neoplastic, Phenotype, Oncology, chemistry, Cell culture, Tumor progression, biology.protein, Tumor necrosis factor alpha, Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+), HeLa Cells
Abstract

Deregulated expression of glycolytic enzymes contributes not only to the increased energy demands of transformed cells but also has non-glycolytic roles in tumors. However, the contribution of these non-glycolytic functions in tumor progression remains poorly defined. Here, we show that elevated expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), but not of other glycolytic enzymes tested, increased aggressiveness and vascularization of non-Hodgkin's lymphoma. Elevated GAPDH expression was found to promote nuclear factor-κB (NF-κB) activation via binding to tumor necrosis factor receptor-associated factor-2 (TRAF2), enhancing the transcription and the activity of hypoxia-inducing factor-1α (HIF-1α). Consistent with this, inactive mutants of GAPDH failed to bind TRAF2, enhance HIF-1 activity or promote lymphomagenesis. Furthermore, elevated expression of gapdh mRNA in biopsies from diffuse large B-cell non-Hodgkin's lymphoma patients correlated with high levels of hif-1α, vegf-a, nfkbia mRNA and CD31 staining. Collectively, these data indicate that deregulated GAPDH expression promotes NF-κB-dependent induction of HIF-1α and has a key role in lymphoma vascularization and aggressiveness.

Published
2014

17. Deciphering the Role of Oncogenic MITFE318K in Senescence Delay and Melanoma Progression

Author

Jean-François Ottavi, Brigitte Bressac-de Paillerets, Karine Bille, Gian Marco De Donatis, Guillaume Bossis, Thomas Strub, Mickaël Ohanna, Stéphane Rocchi, Jean-Philippe Lacour, Véronique Hofman, Irwin Davidson, Sandrine Marchetti, Yann Cheli, Marie-Christine Birling, Paul Hofman, Thomas Luc, Jean-Christophe Marine, Frederic Luciano, Fanélie-Marie Jouenne, Marina Boncompagni, Corine Bertolotto, Flavie Luciani, Marie-Françoise Avril, Caroline Bonet, Justine Leclerc, N. Poulalhon, Robert Ballotti, 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), Régulations cellulaires et oncogenèse (RCO), Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Réponses cellulaires au microenvironnement et cancer, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Biologie et pathologies des cellules mélanocytaires : de la pigmentation cutanée aux mélanomes, 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 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), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), AxesSim, Physiopathologie de la survie et de la mort cellulaire et infection virale, French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Dermatologie [CH Lyon-Sud, Pierre-Bénite], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), ERI-21/EA 4319, Laboratoire de Pathologie Clinique et Expérimentale et CRB INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Louis Pasteur [Chartres]-Université de Nice Sophia-Antipolis (UNSA), Service de Dermatologie [Nice], Hôpital Archet 2 [Nice] (CHU), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie intégrative des tumeurs (UMR 1186), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), This work was funded by la Société Française de Dermatologie, Melanoma Research Alliance (MRA Team Science Award #269626), ANR-13-BSV1-0025-01 to RB, Fondation pour la Recherche Médicale, La Ville de Nice, Cancéropôle PACA to CB, INCa grant 2013-1-MELA-05 to BBdP, Grant Fondation Gustave Roussy 2009, No. PRI-2010-18 to BBdP, Grant 2011 ITMO-Plan Cancer to BBdP, ICGC No. 201102 to BBdP., ANR-13-BSV1-0025,MITF-SUMOcode,Role de la SUMOylation de MITF (Microphthalmia associated Transcription Factor) dans la pigmentation cutanée, et le développement des nævus.(2013), 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 Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), BERTOLOTTO-BALLOTTI, BERTOLOTTO-BALLOTTI, and Blanc 2013 - Role de la SUMOylation de MITF (Microphthalmia associated Transcription Factor) dans la pigmentation cutanée, et le développement des nævus. - - MITF-SUMOcode2013 - ANR-13-BSV1-0025 - Blanc 2013 - VALID

Subjects
0301 basic medicine, Senescence, Adult, Proto-Oncogene Proteins B-raf, Cancer Research, Skin Neoplasms, Primary Cell Culture, Endogeny, [SDV.CAN]Life Sciences [q-bio]/Cancer, Proximity ligation assay, Biology, Melanin, 03 medical and health sciences, Mice, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, Nevus, Animals, Humans, Melanoma, Cellular Senescence, Germ-Line Mutation, Aged, Microphthalmia-Associated Transcription Factor, integumentary system, PTEN Phosphohydrolase, Sumoylation, Middle Aged, medicine.disease, Microphthalmia-associated transcription factor, 3. Good health, body regions, Disease Models, Animal, 030104 developmental biology, Oncology, Cancer research, Melanocytes, Transcriptome
Abstract

International audience; BACKGROUND:MITF encodes an oncogenic lineage-specific transcription factor in which a germline mutation ( MITFE318K ) was identified in human patients predisposed to both nevus formation and, among other tumor types, melanoma. The molecular mechanisms underlying the oncogenic activity of MITF E318K remained uncharacterized.METHODS:Here, we compared the SUMOylation status of endogenous MITF by proximity ligation assay in melanocytes isolated from wild-type (n = 3) or E318K (n = 4) MITF donors. We also used a newly generated Mitf E318K knock-in (KI) mouse model to assess the role of Mitf E318K (n = 7 to 13 mice per group) in tumor development in vivo and performed transcriptomic analysis of the tumors to identify the molecular mechanisms. Finally, using immortalized or normal melanocytes (wild-type or E318K MITF, n = 2 per group), we assessed the role of MITF E318K on the induction of senescence mediated by BRAF V600E . All statistical tests were two-sided.RESULTS:We demonstrated a decrease in endogenous MITF SUMOylation in melanocytes from MITF E318K patients (mean of cells with hypoSUMOylated MITF, MITF E318K vs MITF WT , 94% vs 44%, difference = 50%, 95% CI = 21.8% to 67.2%, P = .004). The Mitf E318K mice were slightly hypopigmented (mean melanin content Mitf WT vs Mitf E318K/+ , 0.54 arbitrary units [AU] vs 0.36 AU, difference = -0.18, 95% CI = -0.36 to -0.007, P = .04). We provided genetic evidence that Mitf E318K enhances BRaf V600E -induced nevus formation in vivo (mean nevus number for Mitf E318K , BRaf V600E vs Mitf WT , BRaf V600E , 68 vs 44, difference = 24, 95% CI = 9.1 to 38.9, P = .006). Importantly, although Mitf E318K was not sufficient to cooperate with BRaf V600E alone in promoting metastatic melanoma, it accelerated tumor formation on a BRaf V600E , Pten-deficient background (median survival, Mitf E318K/+ = 42 days, 95% CI = 31 to 46 vs Mitf WT = 51 days, 95% CI = 50 to 55, P

Published
2017

18. The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML

Author

Eric Solary, Grégory Michel, Arnaud Jacquel, Patrick Auberger, Sandrine Marchetti, Sandrine Obba, Bernard Robaye, Mohamed-Amine Hamouda, Guillaume Robert, Nathalie Droin, Frederic Luciano, Laurent Boyer, Anja Pfeifer, Marc Foretz, Thomas Cluzeau, Dorothée Selimoglu-Buet, Zoheir Hizir, Benoit Viollet, Diogo Gonçalvès, Michael Cerezo, Stéphane Rocchi, and Laurence Legros

Subjects
Macrophage colony-stimulating factor, Cellular differentiation, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Biology, AMP-Activated Protein Kinases, P2RY6, Models, Biological, Monocytes, Uridine Diphosphate, Cell Line, Tumor, Autophagy, Macrophage, Animals, Humans, Receptor, Molecular Biology, Phospholipase C gamma, Receptors, Purinergic P2, Macrophage Colony-Stimulating Factor, Cell Differentiation, Cell Biology, Basic Research Paper, Cell biology, Enzyme Activation, Mice, Inbred C57BL, Leukemia, Myeloid, Monocyte differentiation, Signal transduction, Signal Transduction
Abstract

Autophagy is induced during differentiation of human monocytes into macrophages that is mediated by CSF1/CSF-1/M-CSF (colony stimulating factor 1 [macrophage]). However, little is known about the molecular mechanisms that link CSF1 receptor engagement to the induction of autophagy. Here we show that the CAMKK2-PRKAA1-ULK1 pathway is required for CSF1-induced autophagy and human monocyte differentiation. We reveal that this pathway links P2RY6 to the induction of autophagy, and we decipher the signaling network that links the CSF1 receptor to P2RY6-mediated autophagy and monocyte differentiation. In addition, we show that the physiological P2RY6 ligand UDP and the specific P2RY6 agonist MRS2693 can restore normal monocyte differentiation through reinduction of autophagy in primary myeloid cells from some but not all chronic myelomonocytic leukemia (CMML) patients. Collectively, our findings highlight an essential role for PRKAA1-mediated autophagy during differentiation of human monocytes and pave the way for future therapeutic interventions for CMML.

Published
2015

19. Escherichia coli α-Hemolysin Counteracts the Anti-Virulence Innate Immune Response Triggered by the Rho GTPase Activating Toxin CNF1 during Bacteremia

Author

Mamady Diabate, Patrick Munro, Elsa Garcia, Arnaud Jacquel, Gregory Michel, Sandrine Obba, Diogo Goncalves, Carmelo Luci, Sandrine Marchetti, Dieter Demon, Clara Degos, Yassina Bechah, Jean-Louis Mege, Mohamed Lamkanfi, Patrick Auberger, Jean-Pierre Gorvel, Lynda Maria Stuart, Luce Landraud, Emmanuel Lemichez, Laurent Boyer, 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), Laboratoire de Bactériologie, CHU de Nice, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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), Department of Medical Protein Research, Universiteit Gent = Ghent University [Belgium] (UGENT), 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), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Benaroya Research Institute at Virginia Mason, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, 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), 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), Universiteit Gent = Ghent University (UGENT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), and HAL AMU, Administrateur

Subjects
BACTERIAL, INTERLEUKIN-1-BETA CONVERTING-ENZYME, QH301-705.5, Virulence Factors, Bacterial Toxins, Interleukin-1beta, PROTEIN, Bacteremia, Hemolysin Proteins, Mice, Escherichia coli, Animals, Biology (General), Escherichia coli Infections, CASPASE-1, Mice, Knockout, Mice, Inbred BALB C, PATHOGENS, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Virulence, Escherichia coli Proteins, Biology and Life Sciences, RC581-607, Immunity, Innate, Mice, Inbred C57BL, Disease Models, Animal, INFLAMMASOME, Host-Pathogen Interactions, PROTEASOMAL DEGRADATION, Female, Immunologic diseases. Allergy, E.-COLI, BLADDER INFECTION, SYSTEM, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction, Research Article
Abstract

The detection of the activities of pathogen-encoded virulence factors by the innate immune system has emerged as a new paradigm of pathogen recognition. Much remains to be determined with regard to the molecular and cellular components contributing to this defense mechanism in mammals and importance during infection. Here, we reveal the central role of the IL-1β signaling axis and Gr1+ cells in controlling the Escherichia coli burden in the blood in response to the sensing of the Rho GTPase-activating toxin CNF1. Consistently, this innate immune response is abrogated in caspase-1/11-impaired mice or following the treatment of infected mice with an IL-1β antagonist. In vitro experiments further revealed the synergistic effects of CNF1 and LPS in promoting the maturation/secretion of IL-1β and establishing the roles of Rac, ASC and caspase-1 in this pathway. Furthermore, we found that the α-hemolysin toxin inhibits IL-1β secretion without affecting the recruitment of Gr1+ cells. Here, we report the first example of anti-virulence-triggered immunity counteracted by a pore-forming toxin during bacteremia., Author Summary The pathogenic potentials of most microbes depend on a repertoire of virulence factors. Despite major progress in the understanding of the molecular mechanisms underlying the activities of bacterial effectors, little is known about how they cooperate during infection to overcome host immune defenses and promote microbial persistence. Here, we investigated the roles of two uropathogenic Escherichia coli (UPEC) effectors that are co-ordinately expressed, α-hemolysin (HlyA) and cytotoxic necrotizing factor 1 (CNF1). We demonstrated that the HlyA toxin is critical for bacterial stability in the blood and showed that one important role of HlyA is to inhibit the CNF1-induced host response. Collectively, these findings reveal why the coordinated activities of HlyA and CNF1 are necessary for the full virulence of UPEC. Moreover, they unravel a HlyA-driven counter-defense mechanism used by bacteria to facilitate their survival.

Published
2015

20. Impact of thymidine phosphorylase surexpression on fluoropyrimidine activity and on tumour angiogenesis

Author

Sandrine Marchetti, Marie-Christine Etienne, Gérard Milano, M. Chazal, Dubreuil A, and Jean-Louis Fischel

Subjects
Antimetabolites, Antineoplastic, Cancer Research, Angiogenesis, Tetrazolium Salts, Biology, Transfection, In vivo, Tumor Cells, Cultured, Animals, Cytotoxic T cell, Pentosyltransferases, Thymidine phosphorylase, Thymidine Phosphorylase, Formazans, Neovascularization, Pathologic, Pyrimidine Phosphorylases, Regular Article, In vitro, Rats, Oncology, Biochemistry, Drug Resistance, Neoplasm, Cell culture, Colonic Neoplasms, Cancer research, Syngenic, Fluorouracil, Floxuridine, Neoplasm Transplantation
Abstract

Tumoral thymidine phosphorylase (TP) appears to play a dual role by being involved in neoangiogenesis and by activating 5FU prodrugs at the tumoral target site. The aim of the study was to investigate more thoroughly these potential physiological and pharmacological roles of TP. A rat carcinoma cell line (PROb) was transfected with TP/PD-ECGF in order to study the effect of the overexpression of this enzyme (1) on the sensitivity of cells to 5′DFUR and 5FU in vitro and (2) on tumour growth in vivo by using a syngenic tumour model in the BDIX rat (hepatic tumours, sub-cutaneous tumours). Cytotoxic effects of 5′DFUR, and to a lesser extent those of 5FU, were enhanced in TP clones as compared to control cells: there was a highly significant correlation between TP activity and in vitro sensitivity to 5’DFUR (r2= 0.91, P = 0.0002, n = 8) and, to a lesser extent, to 5FU (r2= 0.49, P = 0.053, n = 8). The impact of TP transfection on tumour growth was relatively modest and concerned only the initial stages of tumour expansion. Staining of TP tumours for endothelial (factor VIII) cells was always higher than controls. The staining ratio (TP/controls) tended to be reduced as tumours increased in size. The stability of TP expression was checked both in vitro (TP activity measurement) and in vivo (RT-PCR determinations) and there was no loss of TP expression over time which could be advanced to explain the progressive weakening of the impact of TP overexpression on both tumour growth and neoangiogenesis. © 2001 Cancer Research Campaign http://www.bjcancer.com

Published
2001

21. Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response

Author

Ophélie Meynet, Marie Bénéteau, Ludivine A. Pradelli, Jean-Ehrland Ricci, Barbara Zunino, Sandrine Marchetti, Johanna Chiche, Aurore Cornille, Michel Carles, and Marie A. Jacquin

Subjects
Programmed cell death, Antimetabolites, Antineoplastic, Lymphoma, B-Cell, T-Lymphocytes, Blotting, Western, Mice, Transgenic, Kaplan-Meier Estimate, Biology, Deoxyglucose, Lymphocyte Activation, Glycolysis Inhibition, Mice, Immune system, Cell Line, Tumor, Animals, Cytotoxicity, Etoposide, Multidisciplinary, Cell Death, Biological Sciences, Mice, Inbred C57BL, Cell culture, Immunology, Cancer cell, Cancer research, Immunogenic cell death, Drug Therapy, Combination, RNA Interference, Calreticulin, Glycolysis, Ex vivo
Abstract

Most DNA-damaging agents are weak inducers of an anticancer immune response. Increased glycolysis is one of the best-described hallmarks of tumor cells; therefore, we investigated the impact of glycolysis inhibition, using 2-deoxyglucose (2DG), in combination with cytotoxic agents on the induction of immunogenic cell death. We demonstrated that 2DG synergized with etoposide-induced cytotoxicity and significantly increased the life span of immunocompetent mice but not immunodeficient mice. We then established that only cotreated cells induced an efficient tumor-specific T-cell activation ex vivo and that tumor antigen-specific T cells could only be isolated from cotreated animals. In addition, only when mice were immunized with cotreated dead tumor cells could they be protected (vaccinated) from a subsequent challenge using the same tumor in viable form. Finally, we demonstrated that this effect was at least partially mediated through ERp57/calreticulin exposure on the plasma membrane. These data identify that the targeting of glycolysis can convert conventional tolerogenic cancer cell death stimuli into immunogenic ones, thus creating new strategies for immunogenic chemotherapy.

Published
2012

22. Severe thymic atrophy in a mouse model of skin inflammation accounts for impaired TNFR1 signaling

Author

Parvati Gamas, Patrick Auberger, Diogo Gonçalvès, Nathalie Belhacene, Pascal Colosetti, Marie A. Jacquin, Marie Bénéteau, Jean-Ehrland Ricci, Sandrine Marchetti, Arnaud Jacquel, and Abdellilah Wakkach

Subjects
Anatomy and Physiology, Mouse, Dermatitis, Mice, 0302 clinical medicine, T-Lymphocyte Subsets, Immune Physiology, Lymphocyte homeostasis, Molecular Cell Biology, Tyrosine Kinase Signaling Cascade, Apoptotic Signaling Cascade, B-Lymphocytes, 0303 health sciences, Multidisciplinary, Cell Death, Reverse Transcriptase Polymerase Chain Reaction, Animal Models, Flow Cytometry, Signaling Cascades, 3. Good health, src-Family Kinases, Receptors, Tumor Necrosis Factor, Type I, Cytokines, Medicine, Tumor necrosis factor alpha, medicine.symptom, Signal Transduction, Research Article, Genetically modified mouse, Transgene, Science, Immunoblotting, Immunology, Mice, Transgenic, Inflammation, Thymus Gland, Biology, Autoimmune Diseases, 03 medical and health sciences, Model Organisms, Atrophy, Immune system, LYN, In Situ Nick-End Labeling, medicine, Animals, Psoriasis, 030304 developmental biology, Tumor Necrosis Factor-alpha, Immunity, medicine.disease, Bromodeoxyuridine, Clinical Immunology, 030215 immunology
Abstract

Transgenic mice expressing the caspase-cleaved form of the tyrosine kinase Lyn (LynΔN) develop a TNFα-dependent skin disease that accurately recapitulates human psoriasis. Participation of lymphocytes in this disease was confirmed by backcrossing LynΔN mice on a Rag-1 deficient background. The present study was therefore conducted to analyze whether modification of lymphocyte homeostasis does occur and participate in the phenotype of LynΔN mice. We show here that LynΔN mice consistently exhibit thymic atrophy that correlates with both a net decrease in the CD4+/CD8+ Double Positive (DP) and an increase in Single Positive (SP) thymocyte sub-populations, but also display an increase of splenic mature B cell. Interestingly, a normal immune phenotype was rescued in a TNFR1 deficient background. Finally, none of these immune alterations was detected in newborn mice before the onset of inflammation. Therefore, we conclude that chronic inflammation can induce thymic atrophy and perturb spleen homeostasis in LynΔN mice through the increased production of TNFα, LTß and TNFR1 signaling.

Published
2012

23. The caspase-cleaved form of LYN mediates a psoriasis-like inflammatory syndrome in mice

Author

Patrick Auberger, Sébastien Grosso, Sandrine Marchetti, Ludivine A. Pradelli, Abdallah Khemis, Bernard Mari, Jean-Paul Ortonne, Nathalie Belhacene, Claus Johansen, Pascal Colosetti, Lars Iversen, Frederic Luciano, Parvati Gamas, Nicolas Ortonne, Paul Hofman, Marcel Deckert, Jean-Ehrland Ricci, Centre méditérannéen 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), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Equipe labellisée Ligue contre le Cancer, Department of Dermatology, Régulations des réactions immunitaires et inflammatoires, 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), Infection bactérienne, inflammation, et carcinogenèse digestive, 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), Laboratory of Clinical and Experimental Pathology, Centre Hospitalier Universitaire de Nice (CHU Nice), 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), 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), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
Keratinocytes, Biopsy, MESH: NF-kappa B, Gene Expression, MESH: Biopsy, Mice, 0302 clinical medicine, MESH: Animals, Caspase, Cells, Cultured, Skin, 0303 health sciences, MESH: Psoriasis, biology, General Neuroscience, NF-kappa B, Phenotype, MESH: Keratinocytes, src-Family Kinases, 030220 oncology & carcinogenesis, Caspases, Tumor necrosis factor alpha, medicine.symptom, MESH: Cells, Cultured, MESH: Gene Expression, MESH: Mice, Transgenic, caspase, mouse model, Caspase 1, Inflammation, Mice, Transgenic, Thymus Gland, MESH: Phenotype, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, MESH: Skin, LYN, MESH: Mice, Inbred C57BL, medicine, Animals, Humans, Psoriasis, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Lyn, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Caspases, MESH: Humans, General Immunology and Microbiology, Tumor Necrosis Factor-alpha, MESH: Thymus Gland, NFKB1, Mice, Inbred C57BL, MESH: src-Family Kinases, Apoptosis, inflammation, MESH: Gene Deletion, MESH: Tumor Necrosis Factor-alpha, biology.protein, Cancer research, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Gene Deletion
Abstract

Udgivelsesdato: 2009-Aug-19 We showed previously that Lyn is a substrate for caspases, a family of cysteine proteases, involved in the regulation of apoptosis and inflammation. Here, we report that expression of the caspase-cleaved form of Lyn (LynDeltaN), in mice, mediates a chronic inflammatory syndrome resembling human psoriasis. Genetic ablation of TNF receptor 1 in a LynDeltaN background rescues a normal phenotype, indicating that LynDeltaN mice phenotype is TNF-alpha-dependent. The predominant role of T cells in the disease occurring in LynDeltaN mice was highlighted by the distinct improvement of LynDeltaN mice phenotype in a Rag1-deficient background. Using pan-genomic profiling, we also established that LynDeltaN mice show an increased expression of STAT-3 and inhibitory members of the NFkappaB pathway. Accordingly, LynDeltaN alters NFkappaB activity underlying a link between inhibition of NFkappaB and LynDeltaN mice phenotype. Finally, analysis of Lyn expression in human skin biopsies of psoriatic patients led to the detection of Lyn cleavage product whose expression correlates with the activation of caspase 1. Our data identify a new role for Lyn as a regulator of psoriasis through its cleavage by caspases.

Published
2008

24. Post-translational regulation of the ERK phosphatase DUSP6/MKP3 by the mTOR pathway

Author

Sandrine Marchetti, Clotilde Gimond, O. Bermudez, Gilles Pagès, Institut de signalisation, biologie du développement et cancer (ISBDC), 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), Physiopathologie de la survie et de la mort cellulaire et infection virale, Université Nice Sophia Antipolis (... - 2019) (UNS), and 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)

Subjects
MAPK/ERK pathway, MESH: Signal Transduction, Cancer Research, Phosphatase, MESH: Insulin-Like Growth Factor I, DUSP6, MESH: Cricetinae, [SDV.CAN]Life Sciences [q-bio]/Cancer, mTORC2, 03 medical and health sciences, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Dual Specificity Phosphatase 6, Cricetinae, Genetics, Animals, MESH: Animals, Insulin-Like Growth Factor I, Phosphorylation, Molecular Biology, MESH: Protein Kinases, PI3K/AKT/mTOR pathway, Cells, Cultured, 030304 developmental biology, 0303 health sciences, biology, MESH: Phosphorylation, Kinase, TOR Serine-Threonine Kinases, RPTOR, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: 1-Phosphatidylinositol 3-Kinase, Cell biology, 030220 oncology & carcinogenesis, MESH: Protein Processing, Post-Translational, biology.protein, Cancer research, MESH: Dual Specificity Phosphatase 6, Protein Kinases, Protein Processing, Post-Translational, MESH: Cells, Cultured, Signal Transduction
Abstract

MAP kinases phosphatases (MKPs) belong to the dual-specificity phosphatase family (DUSP) and dephosphorylate phosphothreonine and phosphotyrosine within MAP kinases. We had previously shown that DUSP6/MKP-3 was phosphorylated and degraded upon growth factor stimulation, in a MEK-dependent manner. Here we show that another pathway involved in growth factor signaling, the PI3K/mTOR signaling pathway, accounts for a part of the phosphorylation and degradation of DUSP6 induced by serum growth factors, as evidenced by experiments using pharmacological inhibitors of PI3 kinase and mammalian target of rapamycin (mTOR). Moreover, specific agonists of the mTOR pathway, such as amino acids or insulin/IGF-1, which do not activate extracellular signal regulated kinases (ERKs) in our cellular model, were also able to induce the phosphorylation and degradation of DUSP6. However, a basal activity of MEK was required for the mTOR pathway-mediated phosphorylation to occur. Mutagenesis studies identified serine 159 within DUSP6 as the target of the mTOR pathway. The ERK phosphatase DUSP6 may thus constitute a novel branch-point of the crosstalk between two major signaling pathways induced by growth factors, the MEK/ERK pathway and the PI3K/mTOR pathway.

Published
2008

25. Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation

Author

Jacques Pouysségur, Gilles Pagès, Jean-Claude Chambard, Clotilde Gimond, Sandrine Marchetti, Thomas Touboul, Danièle Roux, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
MESH: Signal Transduction, MESH: Enzyme Stability, MAP Kinase Kinase 2, MAP Kinase Kinase 1, Serine, 0302 clinical medicine, Enzyme Stability, MESH: Animals, Phosphorylation, Mitogen-Activated Protein Kinase 1, 0303 health sciences, Mitogen-Activated Protein Kinase 3, Kinase, MESH: Proteasome Endopeptidase Complex, Cell biology, MESH: Mutagenesis, Site-Directed, Biochemistry, 030220 oncology & carcinogenesis, MESH: Dual Specificity Phosphatase 6, MESH: MAP Kinase Kinase 2, MESH: MAP Kinase Kinase 1, MESH: Mitogen-Activated Protein Kinase 3, Signal Transduction, MESH: Mitogen-Activated Protein Kinase 1, Proteasome Endopeptidase Complex, Recombinant Fusion Proteins, Phosphatase, DUSP6, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Protein Tyrosine Phosphatases, Biology, Cell Line, 03 medical and health sciences, Dual Specificity Phosphatase 6, MESH: Recombinant Fusion Proteins, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, c-Raf, MESH: Serine, Molecular Biology, 030304 developmental biology, Serine/threonine-specific protein kinase, MESH: Phosphorylation, Cell Biology, Fusion protein, MESH: Cell Line, Mutagenesis, Site-Directed, biology.protein, Protein Tyrosine Phosphatases
Abstract

International audience; Mitogen-activated protein (MAP) kinase phosphatases (MKPs) are dual-specificity phosphatases that dephosphorylate phosphothreonine and phosphotyrosine residues within MAP kinases. Here, we describe a novel posttranslational mechanism for regulating MKP-3/Pyst1/DUSP6, a member of the MKP family that is highly specific for extracellular signal-regulated kinase 1 and 2 (ERK1/2) inactivation. Using a fibroblast model in which the expression of either MKP-3 or a more stable MKP-3-green fluorescent protein (GFP) chimera was induced by tetracycline, we found that serum induces the phosphorylation of MKP-3 and its subsequent degradation by the proteasome in a MEK1 and MEK2 (MEK1/2)-ERK1/2-dependent manner. In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197. Tetracycline-inducible cell clones expressing either single or double serine mutants of MKP-3 or MKP-3-GFP confirmed that these two sites are targeted by the MEK1/2-ERK1/2 module in vivo. Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3. Hence, double mutation caused a threefold increase in the half-life of MKP-3. Finally, we show that the phosphorylation of MKP-3 has no effect on its catalytic activity. Thus, ERK1/2 exert a positive feedback loop on their own activity by promoting the degradation of MKP-3, one of their major inactivators in the cytosol, a situation opposite to that described for the nuclear phosphatase MKP-1.

Published
2005

26. Endothelial cells genetically selected from differentiating mouse embryonic stem cells incorporate at sites of neovascularization in vivo

Author

Sandrine Marchetti, Jacques Pouysségur, Christine Bourcier, Gilles Pagès, Kristiina Iljin, Kari Alitalo, and Clotilde Gimond

Subjects
CD31, Smooth muscle cell differentiation, CD34, Mice, Nude, Neovascularization, Physiologic, Receptors, Cell Surface, Embryoid body, Transfection, Cell Line, Receptors, TIE, Mice, Antigens, CD, Animals, Endothelium, Progenitor cell, CD40, Neovascularization, Pathologic, biology, Stem Cells, Receptor Protein-Tyrosine Kinases, Cell Differentiation, Receptor, TIE-1, Cell Biology, Cadherins, Molecular biology, Embryonic stem cell, Endothelial stem cell, Gene Expression Regulation, biology.protein, Puromycin, Neoplasm Transplantation
Abstract

Large scale purification of endothelial cells is of great interest as it could improve tissue transplantation, reperfusion of ischemic tissues and treatment of pathologies in which an endothelial cell dysfunction exists. In this study, we describe a novel genetic approach that selects for endothelial cells from differentiating embryonic stem (ES) cells. Our strategy is based on the establishment of ES-cell clones that carry an integrated puromycin resistance gene under the control of a vascular endothelium-specific promoter, tie-1. Using EGFP as a reporter gene, we first confirmed the endothelial specificity of the tie-1 promoter in the embryoid body model and in cells differentiated in 2D cultures. Subsequently, tie-1-EGFP ES cells were used as recipients for the tie-1-driven puror transgene. The resulting stable clones were expanded and differentiated for seven days in the presence of VEGF before puromycin selection. As expected, puromycin-resistant cells were positive for EGFP and also expressed several endothelial markers, including CD31, CD34,VEGFR-1, VEGFR-2, Tie-1, VE-cadherin and ICAM-2. Release from the puromycin selection resulted in the appearance of α-smooth muscle actin-positive cells. Such cells became more numerous when the population was cultured on laminin-1 or in the presence of TGF-β1, two known inducers of smooth muscle cell differentiation. The hypothesis that endothelial cells or their progenitors may differentiate towards a smooth muscle cell phenotype was further supported by the presence of cells expressing both CD31 andα-smooth muscle actin markers. Finally, we show that purified endothelial cells can incorporate into the neovasculature of transplanted tumors in nude mice. Taken together, these results suggest that application of endothelial lineage selection to differentiating ES cells may become a useful approach for future pro-angiogenic and endothelial cell replacement therapies.

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