Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis

Aveline Filliol, Yoshinobu Saito, Ajay Nair, Dianne H. Dapito, Le-Xing Yu, Aashreya Ravichandra, Sonakshi Bhattacharjee, Silvia Affo, Naoto Fujiwara, Hua Su, Qiuyan Sun, Thomas M. Savage, John R. Wilson-Kanamori, Jorge M. Caviglia, LiKang Chin, Dongning Chen, Xiaobo Wang, Stefano Caruso, Jin Ku Kang, Amit Dipak Amin, Sebastian Wallace, Ross Dobie, Deqi Yin, Oscar M. Rodriguez-Fiallos, Chuan Yin, Adam Mehal, Benjamin Izar, Richard A. Friedman, Rebecca G. Wells, Utpal B. Pajvani, Yujin Hoshida, Helen E. Remotti, Nicholas Arpaia, Jessica Zucman-Rossi, Michael Karin, Neil C. Henderson, Ira Tabas and Robert F. Schwabe ()
Additional contact information
Aveline Filliol: Columbia University
Yoshinobu Saito: Columbia University
Ajay Nair: Columbia University
Dianne H. Dapito: Columbia University
Le-Xing Yu: Columbia University
Aashreya Ravichandra: Columbia University
Sonakshi Bhattacharjee: Columbia University
Silvia Affo: Columbia University
Naoto Fujiwara: University of Texas Southwestern Medical Center
Hua Su: University of California, San Diego
Qiuyan Sun: Columbia University
Thomas M. Savage: Columbia University Irving Medical Center
John R. Wilson-Kanamori: University of Edinburgh
Jorge M. Caviglia: Columbia University
LiKang Chin: University of Pennsylvania
Dongning Chen: University of Pennsylvania
Xiaobo Wang: Columbia University
Stefano Caruso: Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris
Jin Ku Kang: Columbia University
Amit Dipak Amin: Columbia University
Sebastian Wallace: University of Edinburgh
Ross Dobie: University of Edinburgh
Deqi Yin: Columbia University
Oscar M. Rodriguez-Fiallos: Columbia University
Chuan Yin: Columbia University
Adam Mehal: Columbia University
Benjamin Izar: Columbia University
Richard A. Friedman: Columbia University Irving Medical Center
Rebecca G. Wells: University of Pennsylvania
Utpal B. Pajvani: Columbia University
Yujin Hoshida: University of Texas Southwestern Medical Center
Helen E. Remotti: Columbia University Irving Medical Center
Nicholas Arpaia: Columbia University Irving Medical Center
Jessica Zucman-Rossi: Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris
Michael Karin: University of California, San Diego
Neil C. Henderson: University of Edinburgh
Ira Tabas: Columbia University
Robert F. Schwabe: Columbia University

Nature, 2022, vol. 610, issue 7931, 356-365

Abstract: Abstract Hepatocellular carcinoma (HCC), the fourth leading cause of cancer mortality worldwide, develops almost exclusively in patients with chronic liver disease and advanced fibrosis1,2. Here we interrogated functions of hepatic stellate cells (HSCs), the main source of liver fibroblasts3, 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.

Date: 2022
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DOI: 10.1038/s41586-022-05289-6

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