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Article Dans Une Revue Nature Communications Année : 2021

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

Emilie Crouchet (1) , Simonetta Bandiera (1) , Naoto Fujiwara (2) , Shen Li (3, 4) , Hussein El Saghire (1) , Mirian Fernández-Vaquero (5, 6) , Tobias Riedl (5, 6) , Xiaochen Sun (2) , Hadassa Hirschfield (2) , Frank Jühling (1) , Shijia Zhu (2) , Natascha Roehlen (1) , Clara Ponsolles (1) , Laura Heydmann (1) , Antonio Saviano (1, 7) , Tongqi Qian (2) , Anu Venkatesh (2) , Joachim Lupberger (1) , Eloi R. Verrier (1) , Mozhdeh Sojoodi (3, 4) , Marine A. Oudot (1) , François H. T. Duong (1, 8) , Ricard Masia (3) , Lan Wei (3, 4) , Christine Thumann (1) , Sarah C. Durand (1) , Victor González-Motos (1) , Danijela Heide (5) , Jenny Hetzer (5) , Shigeki Nakagawa (2) , Atsushi Ono (9) , Won-Min Song (10) , Takaaki Higashi (11) , Roberto Sanchez (10) , Rosa S. Kim (10) , C. Billie Bian (10) , Karun Kiani (4, 12) , Tom Croonenborghs (4, 12, 13) , Aravind Subramanian (4) , Raymond T. Chung (3, 4) , Beate K. Straub (14) , Detlef Schuppan (15, 4) , Maliki Ankavay (16) , Laurence Cocquerel (16) , Evelyne Schaeffer (17) , Nicolas Goossens (18) , Anna P. Koh (2) , Milind Mahajan (10) , Venugopalan D. Nair (10) , Ganesh Gunasekaran (10) , Myron E. Schwartz (10) , Nabeel Bardeesy (4) , Alex K. Shalek (12, 19, 20) , Orit Rozenblatt-Rosen (12) , Aviv Regev (12, 19) , Emanuele Felli (1, 7) , Patrick Pessaux (1, 7) , Kenneth K. Tanabe (3, 4) , Mathias Heikenwälder (5) , Catherine Schuster (1) , Nathalie Pochet (4, 12) , Mirjam B. Zeisel (1) , Bryan C. Fuchs (3, 4) , Yujin Hoshida (2) , Thomas F. Baumert (1, 7)
Atsushi Ono
Nabeel Bardeesy
Orit Rozenblatt-Rosen

Résumé

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.

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Cancer
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Dates et versions

hal-03395220 , version 1 (22-10-2021)

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Emilie Crouchet, Simonetta Bandiera, Naoto Fujiwara, Shen Li, Hussein El Saghire, et al.. A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery. Nature Communications, 2021, 12 (1), pp.5525. ⟨10.1038/s41467-021-25468-9⟩. ⟨hal-03395220⟩
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