1. Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer
- Author
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Chang-Jiun Wu, Gillian I. Horwitz, Qing Chang, Hongai Xia, Gerald C. Chu, Ramsey Al-Khalil, Qiuyun Wang, Jianhua Zhang, Timothy P. Heffernan, Alison Liewen, Eliot Fletcher-Sananikone, Avnish Kapoor, Piergiorgio Pettazzoni, Alexei Protopopov, Anguraj Sadanandam, Wantong Yao, Carol Lim, Randy L. Johnson, Giulio Draetta, Ronald A. DePinho, Nora S. Sanchez, Y. Alan Wang, Shan Jiang, Haoqiang Ying, Lynda Chin, Yi Zhong, Baoli Hu, Huamin Wang, Andrea Viale, and Sujun Hua
- Subjects
endocrine system diseases ,Cell ,Cell Cycle Proteins ,medicine.disease_cause ,Mice ,0302 clinical medicine ,media_common ,YAP1 ,0303 health sciences ,Cell Cycle ,TEA Domain Transcription Factors ,Cell cycle ,3. Good health ,DNA-Binding Proteins ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Adenocarcinoma ,KRAS ,E2F Transcription Factors ,Carcinoma, Pancreatic Ductal ,DNA Replication ,media_common.quotation_subject ,Biology ,DNA-binding protein ,General Biochemistry, Genetics and Molecular Biology ,Article ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Pancreatic cancer ,medicine ,Animals ,Humans ,Transcription factor ,neoplasms ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,Biochemistry, Genetics and Molecular Biology(all) ,Addiction ,YAP-Signaling Proteins ,Phosphoproteins ,medicine.disease ,digestive system diseases ,Pancreatic Neoplasms ,Disease Models, Animal ,ras Proteins ,Cancer research ,Transcription Factors - 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.
- Published
- 2014
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