Journal Article

Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis

Pajvani, Utpal B., Remotti, Helen E., Karin, Michael, Mehal, Adam, Henderson, Neil C., Ravichandra, Aashreya, Schwabe, Robert F., Dapito, Dianne H., Amin, Amit Dipak, Zucman-Rossi, Jessica, Tabas, Ira, Wells, Rebecca G., Nair, Ajay, Arpaia, Nicholas, Su, Hua, Wang, Xiaobo, Wallace, Sebastian, Affo, Silvia, Yu, Le-Xing, Caruso, Stefano, Dobie, Ross, Caviglia, Jorge M., Yin, Chuan, Yin, Deqi, Hoshida, Yujin, Rodriguez-Fiallos, Oscar M., Friedman, Richard A., Chin, LiKang, Savage, Thomas M., Fujiwara, Naoto, Wilson-Kanamori, John R., Bhattacharjee, Sonakshi, Kang, Jin Ku, Sun, Qiuyan, Izar, Benjamin, Filliol, Aveline, Chen, Dongning, Saito, Yoshinobu

2022

Overview

Hepatocellular carcinoma (HCC), the fourth leading cause of cancer mortality worldwide, develops almost exclusively in patients with chronic liver disease and advanced fibrosis 1 , 2 . Here we interrogated functions of hepatic stellate cells (HSCs), the main source of liver fibroblasts 3 , during hepatocarcinogenesis. Genetic depletion, activation or inhibition of HSCs in mouse models of HCC revealed their overall tumour-promoting role. HSCs were enriched in the preneoplastic environment, where they closely interacted with hepatocytes and modulated hepatocarcinogenesis by regulating hepatocyte proliferation and death. Analyses of mouse and human HSC subpopulations by single-cell RNA sequencing together with genetic ablation of subpopulation-enriched mediators revealed dual functions of HSCs in hepatocarcinogenesis. Hepatocyte growth factor, enriched in quiescent and cytokine-producing HSCs, protected against hepatocyte death and HCC development. By contrast, type I collagen, enriched in activated myofibroblastic HSCs, promoted proliferation and tumour development through increased stiffness and TAZ activation in pretumoural hepatocytes and through activation of discoidin domain receptor 1 in established tumours. An increased HSC imbalance between cytokine-producing HSCs and myofibroblastic HSCs during liver disease progression was associated with increased HCC risk in patients. In summary, the dynamic shift in HSC subpopulations and their mediators during chronic liver disease is associated with a switch from HCC protection to HCC promotion. Subpopulations of cytokine-producing and myofibroblastic hepatic stellate cells, identified by single-cell RNA sequencing, protect against or promote the development of hepatocellular carcinoma via high expression of hepatocyte growth factor or type I collagen, respectively..

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/2 / 13/31 / 14 / 14/19 / 14/32 / 38 / 45 / 45/29 / 45/77 / 45/90 / 45/91 / 631/67/1504/1610 / 631/67/327 / 64 / 64/110 / 64/60 / 82 / 82/51 / 96 / 96/106 / Ablation / Animal models / Animals / Cancer / Carcinogenesis - pathology / Carcinoma, Hepatocellular - pathology / Cell Proliferation / Cholangiocarcinoma / Collagen (type I) / Collagen Type I - metabolism / Cytokines / Death / Depletion / Discoidin Domain Receptor 1 - metabolism / Disease prevention / Disease Progression / Enrichment / Fibroblasts / Gene sequencing / Genetic engineering / Growth factors / Hepatic Stellate Cells - metabolism / Hepatic Stellate Cells - pathology / Hepatocellular carcinoma / Hepatocyte growth factor / Hepatocyte Growth Factor - metabolism / Hepatocytes / Humanities and Social Sciences / Humans / Life Sciences / Liver / Liver cancer / Liver Cirrhosis - complications / Liver diseases / Liver Neoplasms - pathology / Mice / Mortality / multidisciplinary / Myofibroblasts - pathology / Science / Science (multidisciplinary) / Senescence / Stellate cells / Stiffness / Subpopulations / Transgenic animals / Tumorigenesis / Tumors