Abstract：
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 recently unveiled a previously uncharacterized YES kinase (encoded by YES1)-dependent oncogenic signaling pathway in HCC. To model this subset of HCC, we established a series of syngeneic cell lines from liver tumors of transgenic mice expressing activated human YES. The resulting cell lines (referred to as HepYF) were enriched for expression of stem cell and progenitor markers, proliferated rapidly, and were characterized by high SRC family kinase (SFK) 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. Treatment with sorafenib or the SFK inhibitor dasatinib markedly inhibited the growth of HepYF tumors. The new HepYF HCC cell lines provide relevant preclinical models to study the pathogenesis of HCC and test novel small-molecule inhibitor and immunotherapy approaches.
摘要：
肝细胞癌（HCC）是一种高度未满足的医疗需求的疾病，已成为全球性的健康问题。对HCC发病机制的不完全理解和相关临床前动物模型的数量有限，阻碍了HCC靶向治疗的发展。我们最近公布了一个以前未表征的YES激酶（由YES1编码）在HCC中依赖的致癌信号通路。为了对肝癌的这个子集进行建模，我们从表达激活的人YES的转基因小鼠的肝肿瘤中建立了一系列同系细胞系。所产生的细胞系(称为HepYF)被富集用于表达干细胞和祖细胞标志物。迅速扩散，具有较高的SRC家族激酶（SFK）活性和激活的有丝分裂信号通路。转录组学分析表明，HepYF细胞是HCC最具侵袭性的增殖类别G3亚组的代表。HepYF细胞在原位植入同源宿主后形成快速生长的转移性肿瘤。索拉非尼或SFK抑制剂达沙替尼治疗显著抑制HepYF肿瘤的生长。新的HepYFHCC细胞系提供了相关的临床前模型来研究HCC的发病机理，并测试新的小分子抑制剂和免疫治疗方法。
