Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes

doi:10.1038/s41556-019-0359-5

	Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes
	Sun, Lulu 1; Wang, Yuqing 2; Cen, Jin 1; Ma, Xiaolong 1; Cui, Lei 1; Qiu, Zhixin 1; Zhang, Zhengtao 1; Li, Hong 3; Yang, Run-Zhou 4; Wang, Chenhua 1
刊名	NATURE CELL BIOLOGY
	2019-08-01
卷号	21 期号:8 页码:1015-+
ISSN号	1465-7392
DOI	10.1038/s41556-019-0359-5
通讯作者	Zheng, Yun-Wen(ywzheng@md.tsukuba.ac.jp) ; Zheng, Shan(szheng@shmu.edu.cn) ; Hui, Lijian(ljhui@sibcb.ac.cn)
英文摘要	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.
资助项目	Chinese Academy of Sciences[XDA16020201] ; Chinese Academy of Sciences[XDA12050104] ; Chinese Academy of Sciences[153D31KYSB20160247] ; National Natural Science Foundation of China[31630044] ; National Natural Science Foundation of China[31601186] ; National Natural Science Foundation of China[81703093] ; National Natural Science Foundation of China[31801228] ; Shanghai Science and Technology Committee[16JC1400202] ; National Science and Technology Major Project[2018ZX09711002-009] ; National Special Support Plan for Top Talents
WOS关键词	INTRAHEPATIC CHOLANGIOCARCINOMA ; HEPATOCELLULAR-CARCINOMA ; COLORECTAL-CANCER ; GENE-EXPRESSION ; ADULT LIVER ; CELL ; MITOCHONDRIA ; REVEALS ; MYC ; ENRICHMENT
WOS研究方向	Cell Biology
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000478029000013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289130]
专题	中国科学院上海药物研究所
通讯作者	Zheng, Yun-Wen; Zheng, Shan; Hui, Lijian
作者单位	1.Univ Chinese Acad Sci, Chinese Acad Sci, Ctr Excellence Mol Cell Sci, Shanghai Inst Biochem & Cell Biol,State Key Lab C, Shanghai, Peoples R China 2.Fudan Univ, Dept Pediat Surg, Childrens Hosp, Shanghai, Peoples R China 3.Chinese Acad Sci, CAS MPG Partner Inst Computat Biol, Shanghai Inst Biol Sci, Key Lab Computat Biol, Shanghai, Peoples R China 4.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Shanghai, Peoples R China 5.Chinese Acad Sci, Ctr Drug Safety Evaluat & Res, Shanghai Inst Mat Med, Shanghai, Peoples R China 6.Fudan Univ, Zhongshan Hosp, Dept Pathol, Shanghai, Peoples R China 7.Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Dept Hepat Surg 5, Shanghai, Peoples R China 8.Zhengzhou Univ, Affiliated Hosp 1, Zhengzhou, Henan, Peoples R China 9.Univ Tsukuba, Fac Med, Tsukuba, Ibaraki, Japan 10.Yokohama City Univ, Sch Med, Yokohama, Kanagawa, Japan
推荐引用方式 GB/T 7714	Sun, Lulu,Wang, Yuqing,Cen, Jin,et al. Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes[J]. NATURE CELL BIOLOGY,2019,21(8):1015-+.
APA	Sun, Lulu.,Wang, Yuqing.,Cen, Jin.,Ma, Xiaolong.,Cui, Lei.,...&Hui, Lijian.(2019).Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes.NATURE CELL BIOLOGY,21(8),1015-+.
MLA	Sun, Lulu,et al."Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes".NATURE CELL BIOLOGY 21.8(2019):1015-+.