Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer.
Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer.
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DOI：
10.1016/j.cell.2014.06.003
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发表时间：
2014-07-03
期刊：
影响因子：
64.5
通讯作者：
DePinho RA
中科院分区：
文献类型：
--
作者：
Kapoor A;Yao W;Ying H;Hua S;Liewen A;Wang Q;Zhong Y;Wu CJ;Sadanandam A;Hu B;Chang Q;Chu GC;Al-Khalil R;Jiang S;Xia H;Fletcher-Sananikone E;Lim C;Horwitz GI;Viale A;Pettazzoni P;Sanchez N;Wang H;Protopopov A;Zhang J;Heffernan T;Johnson RL;Chin L;Wang YA;Draetta G;DePinho RA
KRAS的激活突变是各种人类癌症中最常见的事件之一，在人类胰腺导管腺癌（PDAC）中尤为突出。诱导型KrasG 12 D驱动的PDAC小鼠模型已经确立了持续KrasG 12 D表达在肿瘤维持中的关键作用，提供了一种模型来确定KrasG 12 D非依赖性PDAC复发的可能性和潜在机制。在这里，我们发现一些肿瘤发生自发复发，并且缺乏KrasG 12 D表达和下游经典MAPK信号传导，而是获得转录共激活因子Yap 1的扩增和过表达。功能研究确定了Yap 1和转录因子Tead 2在驱动KrasG 12 D非依赖性肿瘤维持中的作用。Yap 1/Tead 2复合物与E2 F转录因子协同作用以激活细胞周期和DNA复制程序。我们的研究，沿着来自人类PDAC模型的确证证据，预示着PDAC中致癌Kras成瘾逃逸的新机制。
Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible KrasG12D-driven mouse model of PDAC has established a critical role for sustained KrasG12D expression in tumor maintenance, providing a model to determine the potential for, and the underlying mechanisms of, KrasG12D–independent PDAC recurrence. Here we show that some tumors undergo spontaneous relapse and are devoid of KrasG12D expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional co-activator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving KrasG12D–independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.
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影响因子：
28.2
作者：
Collisson EA;Trejo CL;Silva JM;Gu S;Korkola JE;Heiser LM;Charles RP;Rabinovich BA;Hann B;Dankort D;Spellman PT;Phillips WA;Gray JW;McMahon M
通讯作者：
McMahon M
DOI：
10.1038/nrc3106
发表时间：
2011-10-13
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
Biankin, Andrew V.;Waddell, Nicola;Kassahn, Karin S.;Gingras, Marie-Claude;Muthuswamy, Lakshmi B.;Johns, Amber L.;Miller, David K.;Wilson, Peter J.;Patch, Ann-Marie;Wu, Jianmin;Chang, David K.;Cowley, Mark J.;Gardiner, Brooke B.;Song, Sarah;Harliwong, Ivon;Idrisoglu, Senel;Nourse, Craig;Nourbakhsh, Ehsan;Manning, Suzanne;Wani, Shivangi;Gongora, Milena;Pajic, Marina;Scarlett, Christopher J.;Gill, Anthony J.;Pinho, Andreia V.;Rooman, Ilse;Anderson, Matthew;Holmes, Oliver;Leonard, Conrad;Taylor, Darrin;Wood, Scott;Xu, Qinying;Nones, Katia;Fink, J. Lynn;Christ, Angelika;Bruxner, Tim;Cloonan, Nicole;Kolle, Gabriel;Newell, Felicity;Pinese, Mark;Mead, R. Scott;Humphris, Jeremy L.;Kaplan, Warren;Jones, Marc D.;Colvin, Emily K.;Nagrial, Adnan M.;Humphrey, Emily S.;Chou, Angela;Chin, Venessa T.;Chantrill, Lorraine A.;Mawson, Amanda;Samra, Jaswinder S.;Kench, James G.;Lovell, Jessica A.;Daly, Roger J.;Merrett, Neil D.;Toon, Christopher;Epari, Krishna;Nguyen, Nam Q.;Barbour, Andrew;Zeps, Nikolajs;Kakkar, Nipun;Zhao, Fengmei;Wu, Yuan Qing;Wang, Min;Muzny, Donna M.;Fisher, William E.;Brunicardi, F. Charles;Hodges, Sally E.;Reid, Jeffrey G.;Drummond, Jennifer;Chang, Kyle;Han, Yi;Lewis, Lora R.;Dinh, Huyen;Buhay, Christian J.;Beck, Timothy;Timms, Lee;Sam, Michelle;Begley, Kimberly;Brown, Andrew;Pai, Deepa;Panchal, Ami;Buchner, Nicholas;De Borja, Richard;Denroche, Robert E.;Yung, Christina K.;Serra, Stefano;Onetto, Nicole;Mukhopadhyay, Debabrata;Tsao, Ming-Sound;Shaw, Patricia A.;Petersen, Gloria M.;Gallinger, Steven;Hruban, Ralph H.;Maitra, Anirban;Iacobuzio-Donahue, Christine A.;Schulick, Richard D.;Wolfgang, Christopher L.;Morgan, Richard A.;Lawlor, Rita T.;Capelli, Paola;Corbo, Vincenzo;Scardoni, Maria;Tortora, Giampaolo;Tempero, Margaret A.;Mann, Karen M.;Jenkins, Nancy A.;Perez-Mancera, Pedro A.;Adams, David J.;Largaespada, David A.;Wessels, Lodewyk F. A.;Rust, Alistair G.;Stein, Lincoln D.;Tuveson, David A.;Copeland, Neal G.;Musgrove, Elizabeth A.;Scarpa, Aldo;Eshleman, James R.;Hudson, Thomas J.;Sutherland, Robert L.;Wheeler, David A.;Pearson, John V.;McPherson, John D.;Gibbs, Richard A.;Grimmond, Sean M.
通讯作者：
Grimmond, Sean M.
影响因子：
50.3
作者：
Hingorani, SR;Petricoin, EF;Tuveson, DA
通讯作者：
Tuveson, DA
DOI：
10.1073/pnas.0601273103
发表时间：
2006-04-11
影响因子：
11.1
作者：
Bardeesy, N;Aguirre, AJ;DePinho, RA
通讯作者：
DePinho, RA