title: Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer.
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.
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Avnish
authors: A
authors: Kapoor
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.|Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Wantong
authors: W
authors: Yao
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.|Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Haoqiang
authors: H
authors: Ying
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Sujun
authors: S
authors: Hua
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Alison
authors: A
authors: Liewen
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Qiuyun
authors: Q
authors: Wang
authors: Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Yi
authors: Y
authors: Zhong
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Chang-Jiun
authors: CJ
authors: Wu
authors: The Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, Surrey, SM2 5NG, U.K.|Swiss Institute for Experimental Cancer Research (ISREC), The Swiss Federal Institute of Technology Lausanne (EPFL), Station 19, CH-1015 Lausanne, Switzerland.
authors: Anguraj
authors: A
authors: Sadanandam
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Baoli
authors: B
authors: Hu
authors: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Qing
authors: Q
authors: Chang
authors: Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
authors: Gerald C
authors: GC
authors: Chu
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Ramsey
authors: R
authors: Al-Khalil
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Shan
authors: S
authors: Jiang
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Hongai
authors: H
authors: Xia
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Eliot
authors: E
authors: Fletcher-Sananikone
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Carol
authors: C
authors: Lim
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Gillian I
authors: GI
authors: Horwitz
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.|Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Andrea
authors: A
authors: Viale
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.|Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Piergiorgio
authors: P
authors: Pettazzoni
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.|Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Nora
authors: N
authors: Sanchez
authors: Department of Pathology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Huamin
authors: H
authors: Wang
authors: Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Alexei
authors: A
authors: Protopopov
authors: Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Jianhua
authors: J
authors: Zhang
authors: Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Timothy
authors: T
authors: Heffernan
authors: Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Randy L
authors: RL
authors: Johnson
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.|Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Lynda
authors: L
authors: Chin
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Y Alan
authors: YA
authors: Wang
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.|Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.|Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Giulio
authors: G
authors: Draetta
authors: Department of Cancer Biology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Ronald A
authors: RA
authors: DePinho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D050684:E2F Transcription Factors / Q000378:metabolism; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D000091102:YAP-Signaling Proteins; D018631:ras Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; C117307:KRAS protein, human; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D000091262:TEA Domain Transcription Factors; C486310:Tead2 protein, mouse; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins