Heterogeneity, inherent and acquired drug resistance in patient-derived organoid models of primary liver cancer

作者：Linfeng Xian, Pei Zhao, Xi Chen, Zhimin Wei, Hongxiang Ji, Jun Zhao, Wenbin Liu, Zishuai Li, Donghong Liu, Xue Han, You‐Wen Qian, Hui Dong, Xiong Zhou, Junyan Fan, Xiaoqiong Zhu, Jianhua Yin, Xiaojie Tan, Dongming Jiang, Hongping Yu, Guangwen Cao · 发表于：Cellular Oncology · 年份：2022 · DOI：10.1007/s13402-022-00707-3 · 被引用次数：61 · 研究领域：Cancer Cells and Metastasis、Liver physiology and pathology、Hepatocellular Carcinoma Treatment and Prognosis

PURPOSE: We aimed to elucidate the applicability of tumor organoids for inherent drug resistance of primary liver cancer (PLC) and mechanisms of acquired drug resistance. METHODS: PLC tissues were used to establish organoids, organoid-derived xenograft (ODX) and patient-derived xenograft (PDX) models. Acquired drug resistance was induced in hepatocellular carcinoma (HCC) organoids. Gene expression profiling was performed by RNA-sequencing. RESULTS: ). Larger tumors, vascular invasion, higher serum AFP levels, advanced stages and upregulation of stemness- and proliferation-related genes were significantly associated with the successful establishment of HCC organoids and PDX. Organoids and ODX recapitulated PLC histopathological features, but were enriched in more aggressive cell types. PLC organoids were mostly resistant to lenvatinib in vitro but sensitive to lenvatinib in ODX models. Stemness- and epithelial-mesenchymal transition (EMT)-related gene sets were found to be upregulated, whereas liver development- and liver specific molecule-related gene sets were downregulated in acquired sorafenib-resistant organoids. Targeting the mTOR signaling pathway was effective in treating acquired sorafenib-resistant HCC organoids, possibly via inducing phosphorylated S6 kinase. Genes upregulated in acquired sorafenib-resistant HCC organoids were associated with an unfavorable prognosis. CONCLUSIONS: HCC organoids perform better than PDX for drug screening. Acquired sorafenib resistanc...