生物
巴基斯坦卢比
转录组
癌变
基因组编辑
计算生物学
瓦博格效应
基因敲除
表型
遗传异质性
重编程
癌症研究
癌症
肿瘤微环境
基因组
癌细胞
基因
细胞生物学
遗传学
基因表达
丙酮酸激酶
糖酵解
生物化学
酶
作者
Mei Tang,Yang Zhao,Jianhui Zhao,Shumei Wei,Mingwei Liu,Nairen Zheng,Didi Geng,Shixun Han,Yuchao Zhang,Guoxuan Zhong,Shuaifeng Li,Xiuming Zhang,Chenliang Wang,Huan Yan,Xiaolei Cao,Li Li,Xueli Bai,Junfang Ji,Xin‐Hua Feng,Jun Qin,Tingbo Liang,Bin Zhao
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2022-06-24
卷期号:8 (25)
被引量:23
标识
DOI:10.1126/sciadv.abn5683
摘要
Mechanistic study and precision treatment of primary liver cancer (PLC) are hindered by marked heterogeneity, which is challenging to recapitulate in any given liver cancer mouse model. Here, we report the generation of 25 mouse models of PLC by in situ genome editing of hepatocytes recapitulating 25 single or combinations of human cancer driver genes. These mouse tumors represent major histopathological types of human PLCs and could be divided into three human-matched molecular subtypes based on transcriptomic and proteomic profiles. Phenotypical characterization identified subtype- or genotype-specific alterations in immune microenvironment, metabolic reprogramming, cell proliferation, and expression of drug targets. Furthermore, single-cell analysis and expression tracing revealed spatial and temporal dynamics in expression of pyruvate kinase M2 ( Pkm2 ). Tumor-specific knockdown of Pkm2 by multiplexed genome editing reversed the Warburg effect and suppressed tumorigenesis in a genotype-specific manner. Our study provides mouse PLC models with defined genetic drivers and characterized phenotypical heterogeneity suitable for mechanistic investigation and preclinical testing.
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