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Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity
Cancer Cell ( IF 48.8 ) Pub Date : 2021-07-21 , DOI: 10.1016/j.ccell.2021.06.016
Joel D Pearson 1 , Katherine Huang 2 , Marek Pacal 2 , Sean R McCurdy 2 , Suying Lu 2 , Arthur Aubry 1 , Tao Yu 2 , Kristine M Wadosky 3 , Letian Zhang 3 , Tao Wang 4 , Alex Gregorieff 5 , Mohammad Ahmad 2 , Helen Dimaras 6 , Ellen Langille 7 , Susan P C Cole 8 , Philippe P Monnier 9 , Benjamin H Lok 10 , Ming-Sound Tsao 11 , Nagako Akeno 12 , Daniel Schramek 7 , Kathryn A Wikenheiser-Brokamp 13 , Erik S Knudsen 14 , Agnieszka K Witkiewicz 15 , Jeffrey L Wrana 7 , David W Goodrich 3 , Rod Bremner 16
Affiliation  

Cancer heterogeneity impacts therapeutic response, driving efforts to discover over-arching rules that supersede variability. Here, we define pan-cancer binary classes based on distinct expression of YAP and YAP-responsive adhesion regulators. Combining informatics with in vivo and in vitro gain- and loss-of-function studies across multiple murine and human tumor types, we show that opposite pro- or anti-cancer YAP activity functionally defines binary YAPon or YAPoff cancer classes that express or silence YAP, respectively. YAPoff solid cancers are neural/neuroendocrine and frequently RB1−/−, such as retinoblastoma, small cell lung cancer, and neuroendocrine prostate cancer. YAP silencing is intrinsic to the cell of origin, or acquired with lineage switching and drug resistance. The binary cancer groups exhibit distinct YAP-dependent adhesive behavior and pharmaceutical vulnerabilities, underscoring clinical relevance. Mechanistically, distinct YAP/TEAD enhancers in YAPoff or YAPon cancers deploy anti-cancer integrin or pro-cancer proliferative programs, respectively. YAP is thus pivotal across cancer, but in opposite ways, with therapeutic implications.



中文翻译:

具有由促癌或抗癌 YAP/TEAD 活动定义的明显弱点的二元泛癌类别

癌症异质性影响治疗反应,推动人们努力发现取代变异性的总体规则。在这里,我们根据 YAP 和 YAP 响应性粘附调节因子的不同表达来定义泛癌二元类。将信息学与多种小鼠和人类肿瘤类型的体内体外功能获得和丧失研究相结合,我们表明相反的促癌或抗癌 YAP 活性在功能上定义了二元 YAP开启或 YAP关闭癌症类别,表达或沉默狂吠,分别。实体癌的YAP是神经/神经内分泌癌,通常是RB1 -/-,如视网膜母细胞瘤、小细胞肺癌和神经内分泌前列腺癌。YAP 沉默是起源细胞固有的,或者是通过谱系转换和耐药性获得的。二元癌症组表现出明显的 YAP 依赖性粘附行为和药物脆弱性,强调了临床相关性。从机制上讲,YAP off或 YAP on cancer中不同的 YAP/TEAD 增强子分别部署了抗癌整合素或促癌增殖程序。因此,YAP 在癌症中起着关键作用,但以相反的方式具有治疗意义。

更新日期:2021-08-09
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