In vitro modeling of hepatocellular carcinoma molecular subtypes for anti-cancer drug assessment.
In vitro modeling of hepatocellular carcinoma molecular subtypes for anti-cancer drug assessment.
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DOI：
10.1038/emm.2017.164
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发表时间：
2018-01-05
影响因子：
12.8
通讯作者：
Hoshida Y
中科院分区：
文献类型：
--
作者：
Hirschfield H;Bian CB;Higashi T;Nakagawa S;Zeleke TZ;Nair VD;Fuchs BC;Hoshida Y
解释肿瘤间分子异质性的易处理的实验模型是抗癌药物开发的关键因素。众所周知，肝细胞癌在肿瘤中表现出高度异质性的分子畸变，包括体细胞遗传和表观遗传学改变。以往的研究表明，由转录组确定的分子肿瘤亚型作为一种全面的功能读数，无论地理和病因变异如何，都可以在全球患者群体中重复观察到。在这里，我们证明了由我们先前对多个临床肝细胞癌队列的转录组荟萃分析确定的转录型肝细胞癌亚型，S1和S2，出现在被研究界广泛使用的一组肝癌细胞系中。有趣的是，在专家组中没有发现与S3亚型基因表达模式相似的细胞系，这代表了侵袭性较弱的肿瘤。MYC途径激活的类S2细胞对具有抗MYC活性的小分子BET溴域抑制剂(+)-JQ1表现出较高的敏感性。这些结果支持使用肝癌细胞系作为评估分子亚型特异性药物反应的模型，这有望导致为肝细胞癌患者提供量身定制的精确护理。
Tractable experimental model that accounts for inter-tumor molecular heterogeneity is a key element of anti-cancer drug development. Hepatocellular carcinoma is known to exhibit highly heterogeneous molecular aberrations across the tumors, including somatic genetic and epigenetic alterations. Previous studies showed that molecular tumor subtypes determined by transcriptome, as a comprehensive functional readout, are reproducibly observed across global patient populations irrespective of geographic and etiological variations. Here we demonstrate that transcriptomic hepatocellular carcinoma subtypes, S1 and S2, determined by our previous transcriptome meta-analysis of multiple clinical hepatocellular carcinoma cohorts, are presented in a panel of hepatoma cell lines widely used by the research community. Interestingly, cell line that resembles gene expression pattern of S3 subtype, representing less aggressive tumors, was not identified in the panel. MYC pathway-activated S2-like cell lines showed higher sensitivity to a small molecule BET bromodomain inhibitor, (+)-JQ1, which has anti-MYC activity. These results support the use of hepatoma cell lines as models to evaluate molecular subtype-specific drug response, which is expected to lead to development of tailored, precision care of the patients with hepatocellular carcinoma.
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影响因子：
11.2
作者：
Hoshida Y;Nijman SM;Kobayashi M;Chan JA;Brunet JP;Chiang DY;Villanueva A;Newell P;Ikeda K;Hashimoto M;Watanabe G;Gabriel S;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR
影响因子：
5.7
作者：
Ikeda M;Ohkawa S;Okusaka T;Mitsunaga S;Kobayashi S;Morizane C;Suzuki I;Yamamoto S;Furuse J
通讯作者：
Furuse J
影响因子：
13.5
作者：
Kawai, HF;Kaneko, S;Kobayashi, K
通讯作者：
Kobayashi, K
影响因子：
5
作者：
Goossens N;Sun X;Hoshida Y
通讯作者：
Hoshida Y
影响因子：
64.8
作者：
Bouhaddou M;DiStefano MS;Riesel EA;Carrasco E;Holzapfel HY;Jones DC;Smith GR;Stern AD;Somani SS;Thompson TV;Birtwistle MR
通讯作者：
Birtwistle MR