Syngeneic mouse model of YES-driven metastatic and proliferative hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a disease of high unmet medical need that has become a global health problem. The development of targeted therapies for HCC has been hindered by the incomplete understanding of HCC pathogenesis and the limited number of relevant preclinical animal models. We have recently unveiled a novel YES-dependent oncogenic signaling pathway in HCC. To model this subset of HCC, we have established a series of syngeneic cell lines from liver tumors of transgenic mice expressing activated YES. The resulting HepYF cell lines were enriched for expression of stem cell/progenitor markers, proliferated rapidly and were characterized by high SRC-family kinase activity and activated mitogenic signaling pathways. Transcriptomic analysis indicated that HepYF cells are representative of the most aggressive proliferation class G3 subgroup of HCC. HepYF cells formed rapidly growing metastatic tumors upon orthotopic implantation into syngeneic hosts. We compared the transcriptomes of primary mouse hepatocytes and cancer cells isolated from murine liver tumors expression activated Yes Y537F.