16 results on '"Noblet, Bénédicte"'
Search Results
2. Corrigendum to: ‘Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target’ [J Hepatol 2021 (74) 1155-1166]
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Ningarhari, Massih, primary, Caruso, Stefano, additional, Hirsch, Théo Z., additional, Bayard, Quentin, additional, Franconi, Andrea, additional, Védie, Anne-Laure, additional, Noblet, Bénédicte, additional, Blanc, Jean-Frédéric, additional, Amaddeo, Giuliana, additional, Ganne, Nathalie, additional, Ziol, Marianne, additional, Paradis, Valérie, additional, Guettier, Catherine, additional, Calderaro, Julien, additional, Morcrette, Guillaume, additional, Kim, Youngsoo, additional, MacLeod, A. Robert, additional, Nault, Jean-Charles, additional, Rebouissou, Sandra, additional, and Zucman-Rossi, Jessica, additional
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- 2022
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3. Le lait : produits, composition et consommation en France
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Noblet, Bénédicte
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- 2012
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4. Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target
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Ningarhari, Massih, Caruso, Stefano, Hirsch, Théo, Bayard, Quentin, Franconi, Andrea, Védie, Anne-Laure, Noblet, Bénédicte, Blanc, Jean-Frédéric, Amaddeo, Giuliana, Ganne, Nathalie, Ziol, Marianne, Paradis, Valérie, Guettier, Catherine, Calderaro, Julien, Morcrette, Guillaume, Kim, Youngsoo, Macleod, A. Robert, Nault, Jean-Charles, Rebouissou, Sandra, Zucman-Rossi, Jessica, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Henri Mondor, 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), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Beaujon [AP-HP], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), HAL-SU, Gestionnaire, École Pratique des Hautes Études (EPHE), and CHU Henri Mondor [Créteil]
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Antisense oligonucleotides ,TERT ,Chronic liver disease ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Fibrosis ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,digestive system diseases ,Treatment ,Telomeres ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Liver ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Cancer - Abstract
International audience; Background & Aims: Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. Thus, we aimed to elucidate the role of telomere length maintenance during liver carcinogenesis.Methods: Telomere length was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, as well as clinical and molecular (analyzed by genome, exome, targeted and/or RNA-sequencing) features of HCC. The preclinical efficacy of anti-TERT antisense oligonucleotides (ASO) was assessed in vitro in 26 cell lines and in vivo in a xenograft mouse model.Results: Aging, liver fibrosis, male sex and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC that developed in livers with long telomeres frequently had wild-type TERT with progenitor features and BAP1 mutations. In contrast, HCC that developed on livers with short telomeres were enriched in the non-proliferative HCC class and frequently had somatic TERT promoter mutations. In HCCs, telomere length is stabilized in a narrow biological range around 5.7 kb, similar to non-tumor livers, by various mechanisms that activate TERT expression. Long telomeres are characteristic of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with ASO was efficient in highly proliferative and poorly differentiated cells. Treatment for 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and activation of apoptosis. The therapeutic effect was also obtained in a xenograft mouse model.Conclusions: Telomere maintenance in HCC carcinogenesis is diverse, and is associated with tumor progression and aggressiveness. The efficacy of anti-TERT ASO treatment in cell lines revealed the oncogenic addiction to TERT in HCC, providing a preclinical rationale for anti-TERT ASO treatment in HCC clinical trials.Lay summary: Telomeres are repeated DNA sequences that protect chromosomes and naturally shorten in most adult cells because of the inactivation of the TERT gene, coding for the telomerase enzyme. Here we show that telomere attrition in the liver, modulated by aging, sex, fibrosis and alcohol, associates with specific clinical and molecular features of hepatocellular carcinoma, the most frequent primary liver cancer. We also show that liver cancer is dependent on TERT reactivation and telomere maintenance, which could be targeted through a novel therapeutic approach called antisense oligonucleotides.
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- 2021
5. BAP1 mutations define a specific subgroup of hepatocellular carcinoma with fibrolamellar features and PKA activation Short title: BAP1 HCC have FLC features and activate PKA
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Hirsch, Theo, Negulescu, Ana, Gupta, Barkha, Caruso, Stefano, Noblet, Bénédicte, Couchy, Gabrielle, Bayard, Quentin, Meunier, Léa, Morcrette, Guillaume, Scoazec, Jean-Yves, Blanc, Jean-Frédéric, Amaddeo, Giuliana, Nault, Jean-Charles, Bioulac-Sage, Paulette, Ziol, Marianne, Beaufrère, Aurélie, Paradis, Valérie, Calderaro, Julien, Imbeaud, Sandrine, Zucman-Rossi, Jessica, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’anatomie et de cytologie pathologiques [Gustave Roussy, Villejuif], Institut Gustave Roussy (IGR), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'hépato-gastro-entérologie [APHP Henri Mondor], Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Hôpital Henri Mondor-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Jean Verdier [AP-HP], Service d'anatomie pathologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Service de Pathologie [Hôpital Beaujon - APHP], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Service d'Anatomopathologie [Hôpital Henri Mondor - APHP], CHU Henri Mondor, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), This work was supported by Institut National du Cancer (INCa) with the International Cancer Genome Consortium (ICGC LICA-FR project), INSERM with the « Cancer et Environnement » (plan Cancer), MUTHEC projects (INCa). The group is supported by the Ligue Nationale contre le Cancer (Equipe Labellisée), Labex OncoImmunology (investissement d’avenir), grant IREB, Coup d’Elan de la Fondation Bettencourt-Shueller, the SIRIC CARPEM, FRM prix Rosen, Ligue contrele cancer comité de Paris (prix René et André Duquesne) and Fondation Mérieux., Zucman-Rossi, Jessica, Département de biologie et pathologie médicales [Gustave Roussy], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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liver cancer ,hemic and lymphatic diseases ,BAP1 ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,digestive system diseases ,PRKACA ,fibrolamellar carcinoma - Abstract
International audience; BACKGROUND AND AIMS:DNAJB1-PRKACA fusion is a specific driver event in fibrolamellar carcinoma (FLC), a rare subtype of hepatocellular carcinoma (HCC) occurring in adolescents and young adults. In older patients, molecular determinants of HCC with mixed histological features of HCC and FLC (mixed-FLC/HCC) remain to be discovered.METHODS:A series of 151 liver tumors including 126 HCC, 15 FLC, and 10 mixed-FLC/HCC were analyzed by RNAseq and whole-genome- or whole-exome-sequencing. Western-blots were performed to validate genomics discoveries. Results were validated using the TCGA database.RESULTS:Most of the mixed-FLC/HCC RNAseq clustered in a robust subgroup of 17 tumors all showing mutation or translocation inactivating BAP1 that codes for the BRCA1 associated protein-1. Similar to FLC, BAP1-HCC were significantly enriched in female, tumor fibrosis and the lack of chronic liver disease when compared to non-BAP1-HCC. However, patients were older and with a poorer prognosis than FLC patients. BAP1 tumors were immune hot, showed progenitor features, did not show DNAJB1-PRKACA fusion and were almost all non-mutated for CTNNB1, TP53 and TERT promoter. In contrast, 80% of the BAP1 tumors showed a chromosome gain of PRKACA at 19p13, combined with a loss of PRKAR2A (coding for the inhibitory regulatory subunit of PKA) at 3p21, leading to a high PRKACA/PRKAR2A ratio at the mRNA and protein levels.CONCLUSION:We have characterized a subgroup of BAP1-driven HCC bearing fibrolamellar-like features and a dysregulation of the PKA pathway, which could be at the root of the clinical and histological similarities between BAP1 tumors and DNAJB1-PRKACA FLCs.
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- 2019
6. BAP1 loss in hepatocellular carcinoma is associated to PKA activation and fibrolamellar features
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Hirsch, Theo, primary, Negulescu, Ana, additional, Gupta, Barkha, additional, Caruso, Stefano, additional, Noblet, Bénédicte, additional, Couchy, Gabrielle, additional, Bayard, Quentin, additional, Meunier, Lea, additional, Morcrette, Guillaume, additional, Scoazec, Jean Yves, additional, Blanc, Jean-Frédéric, additional, Amaddeo, Giuliana, additional, Nault, Jean-Charles, additional, Bioulac-Sage, Paulette, additional, Ziol, Marianne, additional, Beaufrère, Aurélie, additional, Paradis, Valérie, additional, Calderaro, Julien, additional, Imbeaud, Sandrine, additional, and Zucman-Rossi, Jessica, additional
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- 2020
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7. Corrigendum to: “BAP1 mutations define a homogeneous subgroup of hepatocellular carcinoma with fibrolamellar-like features and activated PKA” [J Hepatol (2020) 1–13]
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Hirsch, Théo Z., primary, Negulescu, Ana, additional, Gupta, Barkha, additional, Caruso, Stefano, additional, Noblet, Bénédicte, additional, Couchy, Gabrielle, additional, Bayard, Quentin, additional, Meunier, Léa, additional, Morcrette, Guillaume, additional, Scoazec, Jean-Yves, additional, Blanc, Jean-Frédéric, additional, Amaddeo, Giuliana, additional, Nault, Jean-Charles, additional, Bioulac-Sage, Paulette, additional, Ziol, Marianne, additional, Beaufrère, Aurélie, additional, Paradis, Valérie, additional, Calderaro, Julien, additional, Imbeaud, Sandrine, additional, and Zucman-Rossi, Jessica, additional
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- 2020
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8. BAP1 mutations define a homogeneous subgroup of hepatocellular carcinoma with fibrolamellar-like features and activated PKA
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Hirsch, Théo Z., primary, Negulescu, Ana, additional, Gupta, Barkha, additional, Caruso, Stefano, additional, Noblet, Bénédicte, additional, Couchy, Gabrielle, additional, Bayard, Quentin, additional, Meunier, Léa, additional, Morcrette, Guillaume, additional, Scoazec, Jean-Yves, additional, Blanc, Jean-Frédéric, additional, Amaddeo, Giuliana, additional, Nault, Jean-Charles, additional, Bioulac-Sage, Paulette, additional, Ziol, Marianne, additional, Beaufrère, Aurélie, additional, Paradis, Valérie, additional, Calderaro, Julien, additional, Imbeaud, Sandrine, additional, and Zucman-Rossi, Jessica, additional
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- 2020
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9. Insulin activates hepatic Wnt/β-catenin signaling through stearoyl-CoA desaturase 1 and Porcupine
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Cabrae, Régine, primary, Dubuquoy, Céline, additional, Caüzac, Michèle, additional, Morzyglod, Lucille, additional, Guilmeau, Sandra, additional, Noblet, Bénédicte, additional, Fève, Bruno, additional, Postic, Catherine, additional, Burnol, Anne-Françoise, additional, and Moldes, Marthe, additional
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- 2020
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10. Volasertib preclinical activity in high-risk hepatoblastoma
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Kats, Dina, primary, Ricker, Cora A., additional, Berlow, Noah E., additional, Noblet, Bénédicte, additional, Nicolle, Delphine, additional, Mevel, Katell, additional, Branchereau, Sophie, additional, Judde, Jean-Gabriel, additional, Stiverson, Cody D., additional, Stiverson, Christina L., additional, Svalina, Matthew N., additional, Settelmeyer, Teagan, additional, Matlock, Kevin, additional, Lathara, Melvin, additional, Mussini, Charlotte, additional, Geller, James I., additional, Noakes, Christopher, additional, Sloma, Ido, additional, Bharathy, Narendra, additional, Cairo, Stefano, additional, and Keller, Charles, additional
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- 2019
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11. Insulin activates hepatic Wnt/β-catenin signaling through stearoyl-CoA desaturase 1 and Porcupine
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Cabrae, Régine, Dubuquoy, Céline, Caüzac, Michèle, Morzyglod, Lucille, Guilmeau, Sandra, Noblet, Bénédicte, Fève, Bruno, Postic, Catherine, Burnol, Anne-Francoise, Moldes, Marthe, Bodescot, Myriam, BLANC - Dialogues génétiques et fonctionnels permettant à la signalisation Wnt/beta-caténine de contrôler la balance énergétique dans le foie - - WNT-METABOLIV2010 - ANR-10-BLAN-1116 - BLANC - VALID, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Mice used in this study were housed in an animal facility equipped with the help of the Région Ile de France. R.C. was a recipient of doctoral fellowship from CORDDIM, Ile de France. C.D. and L.M. were recipients of doctoral fellowship from the Ministère de l’Enseignement Supérieur et de la Recherche. C.D. was a recipient from the Fondation pour la Recherche Médicale (Bourse médico-scientifique). This work was performed at the Cochin Institute within the Département Hospitalo-Universitaire (DHU) AUToimmune and HORmonal diseases and was supported by grants from the Fondation pour la Recherche Médicale (FRM Labélisation Équipe, DEQ. 20150331744), from the Agence Nationale de la Recherche (ANR WNT-METABOLIV), from University Paris Descartes and Sorbonne Université, and from INSERM and CNRS., ANR-10-BLAN-1116,WNT-METABOLIV,Dialogues génétiques et fonctionnels permettant à la signalisation Wnt/beta-caténine de contrôler la balance énergétique dans le foie(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP]
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Male ,lcsh:Medicine ,Article ,Fatty Acids, Monounsaturated ,Mice ,Animals ,Insulin ,Homeostasis ,lcsh:Science ,Wnt Signaling Pathway ,beta Catenin ,Lipogenesis ,lcsh:R ,Insulin signalling ,Membrane Proteins ,[SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN] ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Mice, Inbred C57BL ,[SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN] ,Liver ,Hepatocytes ,lcsh:Q ,Sterol Regulatory Element Binding Protein 1 ,Acyltransferases ,Stearoyl-CoA Desaturase - Abstract
International audience; The Wnt/β-catenin pathway plays a pivotal role in liver structural and metabolic homeostasis. Wnt activity is tightly regulated by the acyltransferase Porcupine through the addition of palmitoleate. Interestingly palmitoleate can be endogenously produced by the stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme transcriptionally regulated by insulin. This study aimed to determine whether nutritional conditions, and insulin, regulate Wnt pathway activity in liver. An adenoviral TRE-Luciferase reporter was used as a readout of Wnt/β-catenin pathway activity, in vivo in mouse liver and in vitro in primary hepatocytes. Refeeding enhanced TRE-Luciferase activity and expression of Wnt target genes in mice liver, revealing a nutritional regulation of the Wnt/β-catenin pathway. This effect was inhibited in liver specific insulin receptor KO (iLIRKO) mice and upon wortmannin or rapamycin treatment. Overexpression or inhibition of SCD1 expression regulated Wnt/β-catenin activity in primary hepatocytes. Similarly, palmitoleate added exogenously or produced by SCD1-mediated desaturation of palmitate, induced Wnt signaling activity. Interestingly, this effect was abolished in the absence of Porcupine, suggesting that both SCD1 and Porcupine are key mediators of insulin-induced Wnt/β-catenin activity in hepatocytes. Altogether, our findings suggest that insulin and lipogenesis act as potential novel physiological inducers of hepatic Wnt/β-catenin pathway.
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- 2018
12. Abstract 4628: Tailoring personalized strategies for children with treatment-refractory liver cancer
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Cairo, Stefano, primary, Noblet, Bénédicte, additional, Rasmussen, Samuel, additional, Svalina, Matthew N., additional, Mevel, Katell, additional, Ven, Enora Le, additional, Nicolle, Delphine, additional, Déas, Olivier, additional, Mussini, Charlotte, additional, Branchereau, Sophie, additional, Judde, Jean-Gabriel, additional, and Keller, Charles, additional
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- 2018
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13. Assessment of abuse potential using a simple and translational model of spontaneous withdrawal syndrome in the Sprague–Dawley rat
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Bertaina-Anglade, Valerie, Cayre, Emilie, Noblet, Benedicte, and La Rochelle, Christophe Drieu
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- 2011
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14. FRI515 - BAP1 loss in hepatocellular carcinoma is associated to PKA activation and fibrolamellar features.
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Hirsch, Theo, Negulescu, Ana, Gupta, Barkha, Caruso, Stefano, Noblet, Bénédicte, Couchy, Gabrielle, Bayard, Quentin, Meunier, Lea, Morcrette, Guillaume, Scoazec, Jean Yves, Blanc, Jean-Frédéric, Amaddeo, Giuliana, Nault, Jean-Charles, Bioulac-Sage, Paulette, Ziol, Marianne, Beaufrère, Aurélie, Paradis, Valérie, Calderaro, Julien, Imbeaud, Sandrine, and Zucman-Rossi, Jessica
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HEPATOCELLULAR carcinoma - Published
- 2020
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15. Circulating tumour DNA in patients with hepatocellular carcinoma across tumour stages and treatments.
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Campani C, Imbeaud S, Couchy G, Ziol M, Hirsch TZ, Rebouissou S, Noblet B, Nahon P, Hormigos K, Sidali S, Seror O, Taly V, Ganne Carrie N, Laurent-Puig P, Zucman-Rossi J, and Nault JC
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Objective: Circulating tumour DNA (ctDNA) is a promising non-invasive biomarker in cancer. We aim to assess the dynamic of ctDNA in patients with hepatocellular carcinoma (HCC)., Design: We analysed 772 plasmas from 173 patients with HCC collected at the time of diagnosis or treatment (n=502), 24 hours after locoregional treatment (n=154) and during follow-up (n=116). For controls, 56 plasmas from patients with chronic liver disease without HCC were analysed. All samples were analysed for cell free DNA (cfDNA) concentration, and for mutations in TERT promoter, CTNNB1 , TP53 , PIK3CA and NFE2L2 by sequencing and droplet-based digital PCR. Results were compared with 232 corresponding tumour samples., Results: In patients with active HCC, 40.2% of the ctDNA was mutated vs 14.6% in patients with inactive HCC and 1.8% in controls (p<0.001). In active HCC, we identified 27.5% of mutations in TERT promoter, 21.3% in TP53 , 13.1% in CTNNB1 , 0.4% in PIK3CA and 0.2% in NFE2L2, most of the times similar to those identified in the corresponding tumour. CtDNA mutation rate increased with advanced tumour stages (p<0.001). In 103 patients treated by percutaneous ablation, the presence and number of mutations in the ctDNA before treatment were associated with higher risk of death (p=0.001) and recurrence (p<0.001). Interestingly, cfDNA concentration and detectable mutations increased 24 hours after a locoregional treatment. Among 356 plasmas collected in 53 patients treated by systemic treatments, we detected mutations at baseline in 60.4% of the cases. In patients treated by atezolizumab-bevacizumab, persistence of mutation in ctDNA was associated with radiological progression (63.6% vs 36.4% for disappearance, p=0.019). In two patients progressing under systemic treatments, we detected the occurrence of mutations in CTNNB1 in the plasma that was subclonal in the tumour for one patient and not detectable in the tumour for the other one., Conclusion: ctDNA offers dynamic information reflecting tumour biology. It represents a non-invasive tool useful to guide HCC clinical management., Competing Interests: Competing interests: PN has received honoraria from and/or consults for AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Gilead, Ipsen and Roche. He received research grants from AstraZeneca, AbbVie, Bristol–Myers Squibb and Eisai. NGC received travel and congress fees, consulting fees or honoraria for lectures, presentations, speakers’ bureaus from Abbvie, Bayer, Gilead, Ipsen, Intercept and Roche. J-CN received research funding from Bayer and Ipsen. CC, SI, GC, MZ, TZH, SR, BN, KH, SS, OS, VT, PL-P and JZ-R have nothing to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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16. Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target.
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Ningarhari M, Caruso S, Hirsch TZ, Bayard Q, Franconi A, Védie AL, Noblet B, Blanc JF, Amaddeo G, Ganne N, Ziol M, Paradis V, Guettier C, Calderaro J, Morcrette G, Kim Y, MacLeod AR, Nault JC, Rebouissou S, and Zucman-Rossi J
- Subjects
- Cell Line, Tumor, Drug Discovery, Ethanol metabolism, Humans, Liver Cirrhosis etiology, Liver Cirrhosis metabolism, Oncogene Addiction, Sex Factors, Telomerase genetics, Aging physiology, Carcinogenesis genetics, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular therapy, Liver Neoplasms genetics, Liver Neoplasms metabolism, Liver Neoplasms pathology, Oligonucleotides, Antisense pharmacology, Telomerase metabolism, Telomere Homeostasis drug effects, Telomere Homeostasis physiology
- Abstract
Background & Aims: Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. Thus, we aimed to elucidate the role of telomere length maintenance during liver carcinogenesis., Methods: Telomere length was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, as well as clinical and molecular (analyzed by genome, exome, targeted and/or RNA-sequencing) features of HCC. The preclinical efficacy of anti-TERT antisense oligonucleotides (ASO) was assessed in vitro in 26 cell lines and in vivo in a xenograft mouse model., Results: Aging, liver fibrosis, male sex and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC that developed in livers with long telomeres frequently had wild-type TERT with progenitor features and BAP1 mutations. In contrast, HCC that developed on livers with short telomeres were enriched in the non-proliferative HCC class and frequently had somatic TERT promoter mutations. In HCCs, telomere length is stabilized in a narrow biological range around 5.7 kb, similar to non-tumor livers, by various mechanisms that activate TERT expression. Long telomeres are characteristic of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with ASO was efficient in highly proliferative and poorly differentiated cells. Treatment for 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and activation of apoptosis. The therapeutic effect was also obtained in a xenograft mouse model., Conclusions: Telomere maintenance in HCC carcinogenesis is diverse, and is associated with tumor progression and aggressiveness. The efficacy of anti-TERT ASO treatment in cell lines revealed the oncogenic addiction to TERT in HCC, providing a preclinical rationale for anti-TERT ASO treatment in HCC clinical trials., Lay Summary: Telomeres are repeated DNA sequences that protect chromosomes and naturally shorten in most adult cells because of the inactivation of the TERT gene, coding for the telomerase enzyme. Here we show that telomere attrition in the liver, modulated by aging, sex, fibrosis and alcohol, associates with specific clinical and molecular features of hepatocellular carcinoma, the most frequent primary liver cancer. We also show that liver cancer is dependent on TERT reactivation and telomere maintenance, which could be targeted through a novel therapeutic approach called antisense oligonucleotides., Competing Interests: Conflict of interest Youngsoo Kim and A. Robert MacLeod are part of Ionis Pharmaceuticals, Carlsbad, CA, USA. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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