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

• Published in: Nature communications Vol. 12; no. 1; pp. 5525 - 19
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.09.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/51; 38; 38/47; 38/77; 45/91; 631/114; 631/67/1504/1610/4029; 631/67/69; 631/80/304; 64/60; 64/86; 692/699/1503/1607; 96/106; Animal models; Animals; Cancer; Carcinogenesis - pathology; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Chemoprevention; Cohort Studies; Cyclic AMP - metabolism; Cyclic AMP Response Element-Binding Protein - metabolism; Disease Models, Animal; Drug Discovery; Fibrosis; Gene Expression Regulation, Neoplastic - drug effects; Health services; HEK293 Cells; Hepacivirus - physiology; Hepatitis C - genetics; Hepatocellular carcinoma; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; Histamine; Histamine receptors; Humanities and Social Sciences; Humans; Immunologic Surveillance - drug effects; Inflammation - pathology; Life Sciences; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver cancer; Liver Cirrhosis - pathology; Liver diseases; Liver Neoplasms - pathology; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; Male; Mice; Mice, Knockout; Modelling; Models, Biological; multidisciplinary; Nizatidine - pharmacology; Patients; Perturbation; Prevention; Prognosis; Science; Science (multidisciplinary); Signal Transduction - drug effects; Spheroids; Transcriptome - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25468-9

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. 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.