Identification and validation of a plasticity driver of Combined Hepatocellular-Cholangiocarcinoma using functional interspecies comparison
Identification and validation of a plasticity driver of Combined Hepatocellular-Cholangiocarcinoma using functional interspecies comparison
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使用功能种间比较鉴定和验证联合肝细胞胆管癌的可塑性驱动因素
DOI：
10.1055/s-0041-1740768
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Pellegrino R. Longerich T
中科院分区：
文献类型：
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作者：
Ganjian N;Abadi Z;Trompak O;Geffers R;Zender L;Pellegrino R. Longerich T
肝细胞癌（HCC）和胆管癌（CCA）是两种最常见的原发性肝癌，而HCC-CCA合并（cHCC-CCA）罕见。小鼠的谱系追踪研究表明，胆管癌可能从肝细胞发展而来，而导管细胞也可能由于其可塑性而导致HCC。该项目的目的是确定导致肿瘤细胞表型转换导致cHCC-CCA形成的分子机制。对15例人cHCC-CCA样本的HCC和CCA组分进行外显子组和转录组测序。数据整合鉴定了57个潜在的表型驱动基因，这些基因在两个肿瘤区室之间发生了改变。使用两种基于转座子的嵌合小鼠模型（HCC模型：C57BL/6小鼠的MYC-AKT1； iCCA模型：p19-/-小鼠的KRASG12V）进行体内RNAi筛选以验证候选基因。在组织病理学评估的基础上，单个肿瘤结节显示肿瘤类型的表型开关，测序以鉴定表达的shRNA。
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) represent the two most common types of primary liver cancer, while combined HCC-CCA (cHCC-CCA) is rarely observed. Lineage-tracing studies in mice have shown that cholangiocarcinoma may develop from hepatocytes, while ductular cells may also give rise to HCC as a result of their plasticity. The aim of this project was to identify molecular mechanisms leading to a phenotypic switch in tumor cells resulting in cHCC-CCA formation.Exome and transcriptome sequencing of HCC and CCA components of fifteen human cHCC-CCA samples was conducted. Data integration identified 57 potential phenotypic driver genes which were altered between both tumor compartments. In vivo RNAi screening was used to validate the candidate genes using two transposon-based mosaic mouse models (HCC model: MYC-AKT1 in C57BL/6 mice; iCCA model: KRASG12V in p19-/-mice). Individual tumor nodules displaying a phenotypic switch in tumor type based on histopathological evaluation were sequenced to identify the expressed shRNA.