Transforming primary human hepatocytes into hepatocellular carcinoma with genetically defined factors

Zhiwu Jiang, Lin Cheng, Zhiping Wu, Linfu Zhou, Haitao Wang, Qilan Hong, Qiting Wu, Youguo Long, Yunlin Huang, Gaoqi Xu, Yao Yao, Zhao Yang Tang, Zhenfeng Zhang, Lili Yang, Wei Luo, Jie Yang, Likun Gong, Pentao Liu, Xinwen Chen, Shuzhong Cui, Qi Zhang, Yinxiong Li, Peng Li

EMBO reports

2022, 23, 6, e54275

Peng Li

9.421

 Our understanding of human hepatocellular carcinoma (HCC) development and progression has been hampered by the lack of in vivo models. We performed a genetic screen of 10 oncogenes and genetic mutations in Fah-ablated immunodeficient mice in which primary human hepatocytes (PHHs) are used to reconstitute a functional human liver. We identified that MYC, TP53R249S , and KRASG12D are highly expressed in induced HCC (iHCC) samples. The overexpression of MYC and TP53R249S transform PHHs into iHCC in situ, though the addition of KRASG12D significantly increases the tumorigenic efficiency. iHCC, which recapitulate the histological architecture and gene expression characteristics of clinical HCC samples, reconstituted HCC after serial transplantations. Transcriptomic analysis of iHCC and PHHs showed that MUC1 and FAP are expressed in iHCC but not in normal livers. Chimeric antigen receptor (CAR) T cells against these two surface markers efficiently lyse iHCC cells. The properties of iHCC model provide a biological basis for several clinical hallmarks of HCC, and iHCC may serve as a model to study HCC initiation and to identify diagnostic biomarkers and targets for cellular immunotherapy.