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1. A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery.

Author

Crouchet E, Bandiera S, Fujiwara N, Li S, El Saghire H, Fernández-Vaquero M, Riedl T, Sun X, Hirschfield H, Jühling F, Zhu S, Roehlen N, Ponsolles C, Heydmann L, Saviano A, Qian T, Venkatesh A, Lupberger J, Verrier ER, Sojoodi M, Oudot MA, Duong FHT, Masia R, Wei L, Thumann C, Durand SC, González-Motos V, Heide D, Hetzer J, Nakagawa S, Ono A, Song WM, Higashi T, Sanchez R, Kim RS, Bian CB, Kiani K, Croonenborghs T, Subramanian A, Chung RT, Straub BK, Schuppan D, Ankavay M, Cocquerel L, Schaeffer E, Goossens N, Koh AP, Mahajan M, Nair VD, Gunasekaran G, Schwartz ME, Bardeesy N, Shalek AK, Rozenblatt-Rosen O, Regev A, Felli E, Pessaux P, Tanabe KK, Heikenwälder M, Schuster C, Pochet N, Zeisel MB, Fuchs BC, Hoshida Y, and Baumert TF

Subjects
Animals, Carcinogenesis pathology, Carcinoma, Hepatocellular pathology, Cell Line, Tumor, Chemoprevention, Cohort Studies, Cyclic AMP metabolism, Cyclic AMP Response Element-Binding Protein metabolism, Disease Models, Animal, Gene Expression Regulation, Neoplastic drug effects, HEK293 Cells, Hepacivirus physiology, Hepatitis C genetics, Hepatocytes drug effects, Hepatocytes metabolism, Hepatocytes pathology, Humans, Immunologic Surveillance drug effects, Inflammation pathology, Liver drug effects, Liver metabolism, Liver Cirrhosis pathology, Liver Neoplasms pathology, Macrophages drug effects, Macrophages metabolism, Macrophages pathology, Male, Mice, Knockout, Nizatidine pharmacology, Prognosis, Signal Transduction drug effects, Transcriptome genetics, Mice, Drug Discovery, Liver pathology, Models, Biological
Abstract

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2 + , CLEC5A high , MARCO low liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention., (© 2021. The Author(s).)

Published
2021
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2. Combined Analysis of Metabolomes, Proteomes, and Transcriptomes of Hepatitis C Virus-Infected Cells and Liver to Identify Pathways Associated With Disease Development.

Author

Lupberger J, Croonenborghs T, Roca Suarez AA, Van Renne N, Jühling F, Oudot MA, Virzì A, Bandiera S, Jamey C, Meszaros G, Brumaru D, Mukherji A, Durand SC, Heydmann L, Verrier ER, El Saghire H, Hamdane N, Bartenschlager R, Fereshetian S, Ramberger E, Sinha R, Nabian M, Everaert C, Jovanovic M, Mertins P, Carr SA, Chayama K, Dali-Youcef N, Ricci R, Bardeesy NM, Fujiwara N, Gevaert O, Zeisel MB, Hoshida Y, Pochet N, and Baumert TF

Subjects
Animals, Cell Line, Tumor, Datasets as Topic, Disease Models, Animal, Gene Expression Profiling, Glucose metabolism, Hepatitis C, Chronic metabolism, Hepatitis C, Chronic virology, Hepatocytes transplantation, Hepatocytes virology, Humans, Liver cytology, Liver virology, Metabolomics, Mice, Peroxisomes metabolism, Peroxisomes pathology, Proteomics, STAT3 Transcription Factor metabolism, Transplantation Chimera, Hepacivirus pathogenicity, Hepatitis C, Chronic pathology, Hepatocytes pathology, Liver pathology
Abstract

Background & Aims: The mechanisms of hepatitis C virus (HCV) infection, liver disease progression, and hepatocarcinogenesis are only partially understood. We performed genomic, proteomic, and metabolomic analyses of HCV-infected cells and chimeric mice to learn more about these processes., Methods: Huh7.5.1 dif (hepatocyte-like cells) were infected with culture-derived HCV and used in RNA sequencing, proteomic, metabolomic, and integrative genomic analyses. uPA/SCID (urokinase-type plasminogen activator/severe combined immunodeficiency) mice were injected with serum from HCV-infected patients; 8 weeks later, liver tissues were collected and analyzed by RNA sequencing and proteomics. Using differential expression, gene set enrichment analyses, and protein interaction mapping, we identified pathways that changed in response to HCV infection. We validated our findings in studies of liver tissues from 216 patients with HCV infection and early-stage cirrhosis and paired biopsy specimens from 99 patients with hepatocellular carcinoma, including 17 patients with histologic features of steatohepatitis. Cirrhotic liver tissues from patients with HCV infection were classified into 2 groups based on relative peroxisome function; outcomes assessed included Child-Pugh class, development of hepatocellular carcinoma, survival, and steatohepatitis. Hepatocellular carcinomas were classified according to steatohepatitis; the outcome was relative peroxisomal function., Results: We quantified 21,950 messenger RNAs (mRNAs) and 8297 proteins in HCV-infected cells. Upon HCV infection of hepatocyte-like cells and chimeric mice, we observed significant changes in levels of mRNAs and proteins involved in metabolism and hepatocarcinogenesis. HCV infection of hepatocyte-like cells significantly increased levels of the mRNAs, but not proteins, that regulate the innate immune response; we believe this was due to the inhibition of translation in these cells. HCV infection of hepatocyte-like cells increased glucose consumption and metabolism and the STAT3 signaling pathway and reduced peroxisome function. Peroxisomes mediate β-oxidation of very long-chain fatty acids; we found intracellular accumulation of very long-chain fatty acids in HCV-infected cells, which is also observed in patients with fatty liver disease. Cells in livers from HCV-infected mice had significant reductions in levels of the mRNAs and proteins associated with peroxisome function, indicating perturbation of peroxisomes. We found that defects in peroxisome function were associated with outcomes and features of HCV-associated cirrhosis, fatty liver disease, and hepatocellular carcinoma in patients., Conclusions: We performed combined transcriptome, proteome, and metabolome analyses of liver tissues from HCV-infected hepatocyte-like cells and HCV-infected mice. We found that HCV infection increases glucose metabolism and the STAT3 signaling pathway and thereby reduces peroxisome function; alterations in the expression levels of peroxisome genes were associated with outcomes of patients with liver diseases. These findings provide insights into liver disease pathogenesis and might be used to identify new therapeutic targets., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Published
2019
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3. A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery

Author

Crouchet, Emilie, Bandiera, Simonetta, Fujiwara, Naoto, Li, Shen, El Saghire, Hussein, Fernández-Vaquero, Mirian, Riedl, Tobias, Sun, Xiaochen, Hirschfield, Hadassa, Jühling, Frank, Zhu, Shijia, Roehlen, Natascha, Ponsolles, Clara, Heydmann, Laura, Saviano, Antonio, Qian, Tongqi, Venkatesh, Anu, Lupberger, Joachim, Verrier, Eloi R., Sojoodi, Mozhdeh, Oudot, Marine A., Duong, François H. T., Masia, Ricard, Wei, Lan, Thumann, Christine, Durand, Sarah C., González-Motos, Victor, Heide, Danijela, Hetzer, Jenny, Nakagawa, Shigeki, Ono, Atsushi, Song, Won-Min, Higashi, Takaaki, Sanchez, Roberto, Kim, Rosa S., Bian, C. Billie, Kiani, Karun, Croonenborghs, Tom, Subramanian, Aravind, Chung, Raymond T., Straub, Beate K., Schuppan, Detlef, Ankavay, Maliki, Cocquerel, Laurence, Schaeffer, Evelyne, Goossens, Nicolas, Koh, Anna P., Mahajan, Milind, Nair, Venugopalan D., Gunasekaran, Ganesh, Schwartz, Myron E., Bardeesy, Nabeel, Shalek, Alex K., Rozenblatt-Rosen, Orit, Regev, Aviv, Felli, Emanuele, Pessaux, Patrick, Tanabe, Kenneth K., Heikenwälder, Mathias, Schuster, Catherine, Pochet, Nathalie, Zeisel, Mirjam B., Fuchs, Bryan C., Hoshida, Yujin, Baumert, Thomas F., Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Texas Southwestern Medical Center [Dallas], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Universität Heidelberg [Heidelberg] = Heidelberg University, Nouvel Hôpital Civil de Strasbourg, University Hospital Basel [Basel], Hiroshima University, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Kumamoto University, Broad Institute [Cambridge], Harvard University-Massachusetts Institute of Technology (MIT), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), University Medical Center of the Johannes Gutenberg-University Mainz, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Geneva University Hospital (HUG), Massachusetts Institute of Technology (MIT), Harvard University, This work was supported by ARC, Paris and Institut Hospitalo-Universitaire, Strasbourg (TheraHCC1.0 and 2.0 IHUARC IHU201301187 and IHUARC2019 to T.F.B.), the European Union (ERC-AdG-2014-671231-HEPCIR to T.F.B. and Y.H., EU H2020-667273-HEPCAR to T.F.B. and M.H., and INTERREG-IV-Rhin Supérieur-FEDER-Hepato-Regio-Net 2012 to T.F.B. and M.B.Z), ANRS, Paris (2013/108 and ECTZ103701 to T.F.B), NIH (DK099558 to Y. H., and CA233794 to Y.H. and T. F. B, CA140861 to B.C.F., and CA209940, R21CA209940, and R03AI131066 to N.P. and T.F.B.), Cancer Prevention and Research Institute of Texas (RR180016 to Y.H.), US Department of Defense (W81XWH-16-1-0363 to T.F.B. and Y.H.), the Irma T. Hirschl/Monique Weill-Caulier Trust (Y.H.), and the Foundation of the University of Strasbourg (HEPKIN to T. F. B. and Y. H.) and the Institut Universitaire de France (IUF, T.F.B.). M.H. is supported by an ERC CoG grant (HepatoMetaboPath) and EOS grant and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Project-ID 272983813—TRR 179, and Project-ID 314905040 SFB TR209. This work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS and Inserm Plan Cancer and benefits from funding from the state managed by the French National Research Agency as part of the Investments for the future program., ANR-10-LABX-0028,HepSys,Functional genomics of viral hepatitis and liver disease(2010), European Project: 671231,H2020,ERC-2014-ADG,HEPCIR(2016), European Project: 667273,H2020,H2020-PHC-2015-two-stage,HEP-CAR(2016), Cocquerel, Laurence, Functional genomics of viral hepatitis and liver disease - - HepSys2010 - ANR-10-LABX-0028 - LABX - VALID, Cell circuits as targets and biomarkers for liver disease and cancer prevention - HEPCIR - - H20202016-01-01 - 2020-12-31 - 671231 - VALID, Mechanisms underlying hepatocellular carcinoma pathogenesis and impact of co-morbidities. - HEP-CAR - - H20202016-01-01 - 2019-12-31 - 667273 - VALID, Universität Heidelberg [Heidelberg], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Harvard University [Cambridge], Johannes Gutenberg - Universität Mainz (JGU), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)

Subjects
Liver Cirrhosis, Male, Carcinoma, Hepatocellular, Hepatocellular carcinoma, Carcinogenesis, Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hepacivirus, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Chemoprevention, Models, Biological, Article, Cohort Studies, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Drug Discovery, Cancer genomics, Cyclic AMP, Animals, Humans, Cyclic AMP Response Element-Binding Protein, Immunologic Surveillance, Liver diseases, Nizatidine, Inflammation, Mice, Knockout, Macrophages, Liver Neoplasms, Prognosis, Hepatitis C, Computational biology and bioinformatics, Gene Expression Regulation, Neoplastic, Disease Models, Animal, Mechanisms of disease, HEK293 Cells, Liver, Hepatocytes, Transcriptome, Signal Transduction
Abstract

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention., Drug and target discovery for advanced liver disease are hampered by a lack of suitable models for clinical translation. Here the authors present a human liver cell-based system modeling a clinical prognostic signature allowing to propose nizatidine for treatment of advanced liver fibrosis and hepatocellular carcinoma prevention.

Published
2021

4. miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis

Author

Van Renne, Nicolaas, Roca Suarez, Armando Andres, Duong, Francois H T, Gondeau, Claire, Calabrese, Diego, Fontaine, Nelly, Ababsa, Amina, Bandiera, Simonetta, Croonenborghs, Tom, Pochet, Nathalie, De Blasi, Vito, Pessaux, Patrick, Piardi, Tullio, Sommacale, Daniele, Ono, Atsushi, Chayama, Kazuaki, Fujita, Masashi, Nakagawa, Hidewaki, Hoshida, Yujin, Zeisel, Mirjam B, Heim, Markus H, Baumert, Thomas F, Lupberger, Joachim, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Basel [Basel], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Harvard-MIT Division of Health Sciences and Technology [Cambridge], Massachusetts Institute of Technology (MIT), L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, Université de Reims Champagne-Ardenne (URCA), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Hiroshima University, RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Interaction virus-hôte et maladies du foie, Philips, Alexandre, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Adult, Male, STAT3 Transcription Factor, Carcinoma, Hepatocellular, Carcinogenesis, [SDV]Life Sciences [q-bio], Blotting, Western, Aucun, Down-Regulation, Hepacivirus, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Humans, HEPATOCELLULAR CARCINOMA, RNA, Messenger, ComputingMilieux_MISCELLANEOUS, In Situ Hybridization, Fluorescence, Aged, Aged, 80 and over, Hepatology, Liver Neoplasms, Receptor-Like Protein Tyrosine Phosphatases, Class 2, Middle Aged, Hepatitis C, digestive system diseases, [SDV] Life Sciences [q-bio], MicroRNAs, Liver, SIGNALING, HCV, Hepatocytes, Female, Signal Transduction
Abstract

BACKGROUND AND AIMS: HCV infection is a leading risk factor of hepatocellular carcinoma (HCC). However, even after viral clearance, HCC risk remains elevated. HCV perturbs host cell signalling to maintain infection, and derailed signalling circuitry is a key driver of carcinogenesis. Since protein phosphatases are regulators of signalling events, we aimed to identify phosphatases that respond to HCV infection with relevance for hepatocarcinogenesis. METHODS: We assessed mRNA and microRNA (miRNA) expression profiles in primary human hepatocytes, liver biopsies and resections of patients with HCC, and analysed microarray and RNA-seq data from paired liver biopsies of patients with HCC. We revealed changes in transcriptional networks through gene set enrichment analysis and correlated phosphatase expression levels to patient survival and tumour recurrence. RESULTS: We demonstrate that tumour suppressor protein tyrosine phosphatase receptor delta (PTPRD) is impaired by HCV infection in vivo and in HCC lesions of paired liver biopsies independent from tissue inflammation or fibrosis. In liver tissue adjacent to tumour, high PTPRD levels are associated with a dampened transcriptional activity of STAT3, an increase of patient survival from HCC and reduced tumour recurrence after surgical resection. We identified miR-135a-5p as a mechanistic regulator of hepatic PTPRD expression in patients with HCV. CONCLUSIONS: We previously demonstrated that STAT3 is required for HCV infection. We conclude that HCV promotes a STAT3 transcriptional programme in the liver of patients by suppressing its regulator PTPRD via upregulation of miR-135a-5p. Our results show the existence of a perturbed PTPRD-STAT3 axis potentially driving malignant progression of HCV-associated liver disease.

Published
2018

5. AS032 - A human liver cell-based system modeling a clinical prognostic liver signature combined with single cell RNA-seq for discovery of novel liver disease therapeutics.

Author

Crouchet, Emilie, Bandiera, Simonetta, Fujiwara, Naoto, Li, Shen, El Saghire, Hussein, Sun, Xiaochen, Hirschfield, Hadassa, Roehlen, Natascha, Jühling, Frank, Saviano, Antonio, Gonzalez-Motos, Victor, Venkatesh, Anu, Ponsolles, Clara, Verrier, Eloi, Van Renne, Nicolaas, Lupberger, Joachim, Thumann, Christine, Duong, François H.T., Zhu, Shijia, and Sojoodi, Mozhdeh

Subjects
*RNA sequencing, *LIVER diseases, *LIVER, *THERAPEUTICS
Published
2020
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6. AS143 - Single cell RNA-seq of patient liver tissues uncover HRH2+/CLEC5a high/macro low macrophages as therapeutic target for the treatment of liver fibrosis and cancer prevention.

Author

Crouchet, Emilie, Bandiera, Simonetta, Fujiwara, Naoto, Li, Shen, El Saghire, Hussein, Sun, Xiaochen, Hirschfield, Hadassa, Roehlen, Natascha, Jühling, Frank, Saviano, Antonio, Gonzalez-Motos, Victor, Venkatesh, Anu, Ponsolles, Clara, Lupberger, Joachim, Duong, François H.T., Zhu, Shijia, Sojoodi, Mozhdeh, Masia, Ricard, Wei, Lan, and Oudot, Marine

Subjects
*LIVER cancer, *RNA sequencing, *CANCER prevention, *LIVER, *TISSUES
Published
2020
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