Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity.
Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity.
复制标题
二元泛癌症类别，具有由促癌或抗癌雅普/TEAD活性定义的不同脆弱性。
DOI：
10.1016/j.ccell.2021.06.016
复制
发表时间：
2021-08-09
期刊：
影响因子：
50.3
通讯作者：
Bremner R
中科院分区：
文献类型：
--
作者：
Pearson JD;Huang K;Pacal M;McCurdy SR;Lu S;Aubry A;Yu T;Wadosky KM;Zhang L;Wang T;Gregorieff A;Ahmad M;Dimaras H;Langille E;Cole SPC;Monnier PP;Lok BH;Tsao MS;Akeno N;Schramek D;Wikenheiser-Brokamp KA;Knudsen ES;Witkiewicz AK;Wrana JL;Goodrich DW;Bremner R
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过度规则。在这里，我们根据雅普和YAP反应性粘附调节因子的不同表达来定义泛癌二元分类。将信息学与跨多种鼠和人肿瘤类型的体内和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雅普活性在功能上定义了二元YAPon或YAPoff癌症类别，其分别表达或沉默雅普。YAPoff实体癌是神经/神经内分泌癌，通常是RB 1-/-，如视网膜母细胞瘤、小细胞肺癌和神经内分泌前列腺癌。雅普沉默是起源细胞固有的，或通过谱系转换和耐药性获得。二元癌症组表现出不同的YAP依赖性粘附行为和药物脆弱性，强调临床相关性。在机制上，YAPoff或YAPon癌症中不同的雅普/TEAD增强子分别部署抗癌整联蛋白或促癌增殖程序。因此，雅普在癌症中是关键的，但以相反的方式，具有治疗意义。Pearson等证明，雅普/TAZ是众所周知的癌基因，是一大组癌症中的肿瘤抑制因子。泛癌分析显示，相反的雅普/TAZ表达，粘附行为，致癌与肿瘤抑制雅普/TAZ活性功能分层二元癌症类别，互换驱动耐药性。对比YAPoff/YAPon类表现出独特的弱点，促进治疗选择。
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. Pearson et al. demonstrate that YAP/TAZ, well-known oncogenes, are tumor suppressors in a large group of cancers. Pan-cancer analyses reveal that opposite YAP/TAZ expression, adhesive behavior, and oncogenic versus tumor suppressor YAP/TAZ activity functionally stratify binary cancer classes, which interchange to drive drug resistance. Contrasting YAPoff/YAPon classes exhibit unique vulnerabilities, facilitating therapeutic selection.
登录
查看更多内容
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
p53通过抑制MTOR途径激活来抑制癌的进展。
影响因子：
8
作者：
通讯作者：
--
影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
4.6
作者：
Cahill KM;Huo Z;Tseng GC;Logan RW;Seney ML
通讯作者：
Seney ML