A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery.
Fiche publication
Date publication
septembre 2021
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BAUMERT Thomas, Dr LUPBERGER Joachim, Pr PESSAUX Patrick, Dr CROUCHET Emilie, Dr VERRIER Eloi
Tous les auteurs :
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, Baumert TF
Lien Pubmed
Résumé
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, MARCO 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.
Référence
Nat Commun. 2021 Sep 17;12(1):5525