美国西奈山医院Rod Bremner团队在研究中取得进展。他们定义了具有由促癌或抑癌 YAP / TEAD活性定义的不同易感性二元泛癌类。这一研究成果于2021年7月15日发表在国际顶尖学术期刊《癌细胞》杂志上。

他们根据 YAP 和 YAP 响应粘附调节子的差异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和体外功能获得和丧失研究相结合，他们表明相反的促癌或抑癌YAP 活性在功能上分别定义了表达或沉默 YAP 的二元 YAPon 或 YAPoff 癌症类别. YAPoff 实体瘤是神经/神经内分泌型的，通常是 RB1/，例如视网膜母细胞瘤、小细胞肺癌和神经内分泌前列腺癌。YAP 沉默是起源细胞所固有的，或者是通过谱系转换和耐药性获得的。二元癌症组表现出不同的 YAP 依赖性粘附行为和药物易感性，强调了临床相关性。

从机制上讲，YAPoff 或 YAPon 癌症中不同 YAP / TEAD 增强子分别部署抑癌整合素或促癌增殖程序。因此，YAP 对癌症至关重要，但另一方面也具有治疗意义。

研究人员表示，癌症异质性影响治疗反应，推动了人类努力发现取代变异的总体规则。

附：英文原文

Title: Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity

Author: Joel D. Pearson, Katherine Huang, Marek Pacal, Sean R. McCurdy, Suying Lu, Arthur Aubry, Tao Yu, Kristine M. Wadosky, Letian Zhang, Tao Wang, Alex Gregorieff, Mohammad Ahmad, Helen Dimaras, Ellen Langille, Susan P.C. Cole, Philippe P. Monnier, Benjamin H. Lok, Ming-Sound Tsao, Nagako Akeno, Daniel Schramek, Kathryn A. Wikenheiser-Brokamp, Erik S. Knudsen, Agnieszka K. Witkiewicz, Jeffrey L. Wrana, David W. Goodrich, Rod Bremner

Issue&Volume: 2021-07-15

Abstract: Cancer heterogeneity impacts therapeutic response, driving efforts to discover over-archingrules that supersede variability. Here, we define pan-cancer binary classes basedon distinct expression of YAP and YAP-responsive adhesion regulators. Combining informaticswith 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 binaryYAPon 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 switchingand drug resistance. The binary cancer groups exhibit distinct YAP-dependent adhesivebehavior 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.

DOI: 10.1016/j.ccell.2021.06.016

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00338-X