| Literature DB >> 24954535 |
Avnish Kapoor1, Wantong Yao1,2, Haoqiang Ying1,2, Sujun Hua1, Alison Liewen1, Qiuyun Wang1, Yi Zhong3, Chang-Jiun Wu1, Anguraj Sadanandam4,5, Baoli Hu1, Qing Chang2, Gerald C Chu6, Ramsey Al-Khalil1, Shan Jiang1, Hongai Xia1, Eliot Fletcher-Sananikone1, Carol Lim1, Gillian I Horwitz1, Andrea Viale1,2, Piergiorgio Pettazzoni1,2, Nora Sanchez1,2, Huamin Wang7, Alexei Protopopov3, Jianhua Zhang3, Timothy Heffernan3, Randy L Johnson8, Lynda Chin1,3, Y Alan Wang1, Giulio Draetta1,2,3, Ronald A DePinho9.
Abstract
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 Kras(G12D)-driven mouse model of PDAC has established a critical role for sustained Kras(G12D) expression in tumor maintenance, providing a model to determine the potential for and the underlying mechanisms of Kras(G12D)-independent PDAC recurrence. Here, we show that some tumors undergo spontaneous relapse and are devoid of Kras(G12D) expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving Kras(G12D)-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.Entities:
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Year: 2014 PMID： 24954535 PMCID： PMC4109295 DOI： 10.1016/j.cell.2014.06.003
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582