1. Academic Validation
  2. Establishment of a hepatocellular carcinoma patient-derived xenograft platform and its application in biomarker identification

Establishment of a hepatocellular carcinoma patient-derived xenograft platform and its application in biomarker identification

  • Int J Cancer. 2020 Mar 15;146(6):1606-1617. doi: 10.1002/ijc.32564.
Bo Hu 1 2 Hong Li 3 Wei Guo 1 2 4 Yun-Fan Sun 1 2 Xin Zhang 1 2 Wei-Guo Tang 1 2 Liu-Xiao Yang 1 2 Yang Xu 1 2 Xiao-Yan Tang 3 Guo-Hui Ding 3 Shuang-Jian Qiu 1 2 Jian Zhou 1 2 5 Yi-Xue Li 3 Jia Fan 1 2 5 Xin-Rong Yang 1 2
Affiliations

Affiliations

  • 1 Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
  • 2 Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, People's Republic of China.
  • 3 Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
  • 4 Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
  • 5 Institute of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China.
Abstract

Using a method optimized in hepatocellular carcinoma (HCC), we established patient-derived xenograft (PDX) models with an increased take rate (42.2%) and demonstrated that FBS +10% dimethyl sulfoxide exhibited the highest tumor take rate efficacy. Among 254 HCC patients, 103 stably transplantable xenograft lines that could be serially passaged, cryopreserved and revived were established. These lines maintained the diversity of HCC and the essential features of the original specimens at the histological, transcriptome, proteomic and genomic levels. Tumor engraftment was associated with lack of encapsulation, poor tumor differentiation, large size and overexpression of Cancer stem cell biomarkers, and was an independent predictor for overall survival and tumor recurrence after resection. To confirm the preclinical value of the PDX model in HCC treatment, several antitumor agents were tested in 16 selected PDX models. The results revealed a high degree of pharmacologic heterogeneity in the cohort, as well as heterogeneity to different agents in the same individual. The sorafenib responses observed between HCC patients and the corresponding PDXs were also consistent. After molecular characterization of the PDX models, we explored the predictive markers for sorafenib response and found that mitogen-activated protein kinase kinase kinase 1 (MAP3K1) might play an important role in sorafenib resistance and sorafenib response is impaired in patients with MAP3K1 downexpression. Our results indicated that PDX models could accurately reproduce patient tumors biology and could aid in the discovery of new treatments to advance in precision medicine.

Keywords

MAP3K1; drug resistance; hepatocellular carcinoma; patient-derived tumor grafts; sorafenib.

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