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

• DOI: 10.1038/s41467-021-25468-9
• Publication Date: 2021-09-17T10:04:13Z
• Authors: Emilie Crouchet; Simonetta Bandiera; Naoto Fujiwara; Shen Li; Hussein El Saghire; Mirian Fernández-...; Tobias Riedl; Xiaochen Sun; Hadassa Hirschfield; Frank Jühling; Shijia Zhu; Natascha Roehlen; Clara Ponsolles; Laura Heydmann; Antonio Saviano; Tongqi Qian; Anu Venkatesh; Joachim Lupberger; Eloi R. Verrier; Mozhdeh Sojoodi; Marine A. Oudot; François H. T. Duong; Ricard Masia; Lan Wei; Christine Thumann; Sarah C. Durand; Victor González-M...; Danijela Heide; Jenny Hetzer; Shigeki Nakagawa; Atsushi Ono; Won-Min Song; Takaaki Higashi; Roberto Sanchez; Rosa S. Kim; C. Billie Bian; Karun Kiani; Tom Croonenborghs; Aravind Subramanian; Raymond T. Chung; Beate K. Straub; Detlef Schuppan; Maliki Ankavay; Laurence Cocquerel; Evelyne Schaeffer; Nicolas Goossens; Anna P. Koh; Milind Mahajan; Venugopalan D. Nair; Ganesh Gunasekaran; Myron E. Schwartz; Nabeel Bardeesy; Alex K. Shalek; Orit Rozenblatt-R...; Aviv Regev; Emanuele Felli; Patrick Pessaux; Kenneth K. Tanabe; Mathias Heikenwälder; Catherine Schuster; Nathalie Pochet; Mirjam B. Zeisel; Bryan C. Fuchs; Yujin Hoshida; Thomas F. Baumert
• Keywords: Liver disease; Liver Cancer; Chronic liver disease; Hepatitis C

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 robust human cell-based system modeling clinical prognostic signature (PLS) predicting long-term progression toward HCC. Using the PLS as readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal patient-derived spheroids, identify nizatidine, histamine receptor H2 (HRH2) blocker, for advanced HCC chemoprevention. Moreover, perturbation studies combined single cell RNA-Seq analyses patient tissues uncover hepatocytes HRH2 + , CLEC5A high MARCO low macrophages potential nizatidine targets. model enables discovery urgently needed targets therapeutics cancer prevention.