Liver cancer heterogeneity modeled by in situ genome editing of hepatocytes.
Liver cancer heterogeneity modeled by in situ genome editing of hepatocytes.
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通过肝细胞原位基因组编辑模拟肝癌异质性
DOI：
10.1126/sciadv.abn5683
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发表时间：
2022-06-24
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
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作者：
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. Mouse liver tumor model panel reveals diverse human-matched and therapy-related phenotypical and molecular characters.
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DOI：
10.1093/bioinformatics/btr670
发表时间：
2012-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Boeva V;Popova T;Bleakley K;Chiche P;Cappo J;Schleiermacher G;Janoueix-Lerosey I;Delattre O;Barillot E
通讯作者：
Barillot E
胆管癌：发病机理，诊断和治疗的进展。
影响因子：
13.5
作者：
Blechacz, Boris;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
64.5
作者：
Ding, S;Wu, XH;Xu, T
通讯作者：
Xu, T
影响因子：
158.5
作者：
Finn, Richard S.;Qin, Shukui;Cheng, Ann-Lii
通讯作者：
Cheng, Ann-Lii
影响因子：
7
作者：
Dees ND;Zhang Q;Kandoth C;Wendl MC;Schierding W;Koboldt DC;Mooney TB;Callaway MB;Dooling D;Mardis ER;Wilson RK;Ding L
通讯作者：
Ding L