Functional links between liver fibrosis and liver cancer development and growth - Mechanisms and therapeutic implications

Hepatocellular carcinoma (HCC) develops almost exclusively in patients with chronic liver disease (CLD) and advanced fibrosis/cirrhosis, which constitutes a premalignant condition. Here we sought to interrogate functions of hepatic stellate cells (HSC), the main source of fibroblasts in the injured liver, during hepatocarcinogenesis using clean genetic methods. Genetic depletion, activation or inhibition of HSC revealed tumor-promoting roles of HSC in different HCC models. Interestingly, HSC were enriched in the non-tumor environment. Single cell RNA-sequencing and CellPhoneDB analysis demonstrated that HSC were the cell population that most intensely interacted with hepatocytes in the non-tumor environment in CLD. RNA-sequencing and immunohistochemistry/TUNEL assays demonstrated that HSC modulated hepatocarcinogensis by regulating hepatocyte proliferation and death in the non-tumor environment. Surprisingly, further analysis of mouse and human HSC subpopulations by single cell and single nucleus RNA-sequencing and their associated mediators revealed two populations that mediated dual functions of HSC in hepatocarcinogenesis. Hepatocyte growth factor, enriched in a subpopulations of quiescent and cytokine-producing HSC (cyHSC), protected from hepatocyte death and HCC development. In contrast, type I collagen, enriched in the subpopulation of highly activated myofibroblastic HSC (myHSC), increased stiffness and hepatocyte proliferation, thereby promoting HCC development. In summary, our data suggest that the dynamic shift of HSC subpopulations during CLD and their mediators is associated with a switch from HCC protection to HCC promotion.