Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes
Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes
复制标题
使用直接重编程的人类肝细胞衍生的类器官模拟肝癌的发生
DOI：
10.1038/s41556-019-0359-5
复制
发表时间：
2019-08-01
影响因子：
21.3
通讯作者：
Hui, Lijian
中科院分区：
文献类型：
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作者：
Sun, Lulu;Wang, Yuqing;Hui, Lijian
人类肝癌，包括肝细胞癌和肝内胆管细胞癌，通常诊断较晚，预后较差。更好地了解癌症的发生可以提供潜在的预防性治疗并提高存活率。研究人类肝癌启动的模型在很大程度上是缺失的。在这里，利用直接重编程的人肝细胞(HiHeps)和失活的P53和Rb，我们建立了具有肝脏结构和功能的有机化合物。对HiHep类有机化合物进行了基因工程，以模拟人类肝癌的最初变化。C-Myc的过度表达导致真正的肝细胞癌的发生。C-Myc诱导的线粒体-内质网过度偶联促进了肝细胞癌的发生，似乎是预防性治疗的靶点。此外，通过对人肝内胆管癌细胞富集性突变的分析，我们证明了联合抑制Notch和JAK-STAT可以阻止RAS诱导的肝细胞向肝内胆管癌细胞的谱系转换。总而言之，hiHep有机类化合物代表了一个可以通过基因操作来模拟癌症启动和确定潜在预防疗法的系统。
Human liver cancers, including hepatocellular carcinomas and intra-hepatic cholangiocarcinomas, are often diagnosed late with poor prognosis. A better understanding of cancer initiation could provide potential preventive therapies and increase survival. Models for studying human liver cancer initiation are largely missing. Here, using directly reprogrammed human hepatocytes (hiHeps) and inactivation of p53 and RB, we established organoids possessing liver architecture and function. HiHep organoids were genetically engineered to model the initial alterations in human liver cancers. Bona fide hepatocellular carcinomas were developed by overexpressing c-Myc. Excessive mitochondrion–endoplasmic reticulum coupling induced by c-Myc facilitated hepatocellular carcinoma initiation and seemed to be a target of preventive treatment. Furthermore, through the analysis of human intra-hepatic cholangiocarcinoma-enriched mutations, we demonstrate that the RAS-induced lineage conversion from hepatocytes to intra-hepatic cholangiocarcinoma cells can be prevented by the combined inhibition of Notch and JAK–STAT. Together, hiHep organoids represent a system that can be genetically manipulated to model cancer initiation and identify potential preventive therapies.