Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer

Avnish Kapoor; Wantong Yao; Haoqiang Ying; Sujun Hua; Alison Liewen; Qiuyun Wang; Yi Zhong; Chang-Jiun Wu; Anguraj Sadanandam; Baoli Hu; Qing Chang; Gerald C Chu; Ramsey Al-Khalil; Shan Jiang; Hongai Xia; Eliot Fletcher-Sananikone; Carol Lim; Gillian I Horwitz; Andrea Viale; Piergiorgio Pettazzoni; Nora Sanchez; Huamin Wang; Alexei Protopopov; Jianhua Zhang; Timothy Heffernan; Randy L Johnson; Lynda Chin; Y Alan Wang; Giulio Draetta; Ronald A DePinho

doi:10.1016/j.cell.2014.06.003

Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer

Cell. 2014 Jul 3;158(1):185-197. doi: 10.1016/j.cell.2014.06.003. Epub 2014 Jun 19.

Authors

Avnish Kapoor^#¹, Wantong Yao^#^{1

2}, Haoqiang Ying^#^{1

2}, Sujun Hua¹, Alison Liewen¹, Qiuyun Wang¹, Yi Zhong³, Chang-Jiun Wu¹, Anguraj Sadanandam^{4

5}, Baoli Hu¹, Qing Chang², Gerald C Chu⁶, Ramsey Al-Khalil¹, Shan Jiang¹, Hongai Xia¹, Eliot Fletcher-Sananikone¹, Carol Lim¹, Gillian I Horwitz¹, Andrea Viale^{1

2}, Piergiorgio Pettazzoni^{1

2}, Nora Sanchez^{1

2}, Huamin Wang⁷, Alexei Protopopov³, Jianhua Zhang³, Timothy Heffernan³, Randy L Johnson⁸, Lynda Chin^{1

3}, Y Alan Wang¹, Giulio Draetta^{1

2

3}, Ronald A DePinho⁹

Affiliations

¹ Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
² Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
³ Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
⁴ The Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, Surrey, SM2 5NG, U.K.
⁵ Swiss Institute for Experimental Cancer Research (ISREC), The Swiss Federal Institute of Technology Lausanne (EPFL), Station 19, CH-1015 Lausanne, Switzerland.
⁶ Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
⁷ Department of Pathology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
⁸ Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
⁹ Department of Cancer Biology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism*
Adenocarcinoma / metabolism*
Adenocarcinoma / pathology
Animals
Carcinoma, Pancreatic Ductal / metabolism*
Carcinoma, Pancreatic Ductal / pathology
Cell Cycle
Cell Cycle Proteins
Cell Line, Tumor
DNA Replication
DNA-Binding Proteins / metabolism
Disease Models, Animal
E2F Transcription Factors / metabolism
Humans
Mice
Pancreatic Neoplasms / metabolism*
Pancreatic Neoplasms / pathology
Phosphoproteins / metabolism*
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins p21(ras) / metabolism*
TEA Domain Transcription Factors
Transcription Factors / metabolism
YAP-Signaling Proteins
ras Proteins / metabolism

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
DNA-Binding Proteins
E2F Transcription Factors
KRAS protein, human
Phosphoproteins
Proto-Oncogene Proteins
TEA Domain Transcription Factors
Tead2 protein, mouse
Transcription Factors
YAP-Signaling Proteins
Yap1 protein, mouse
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)
ras Proteins

Associated data

GEO/GSE53169

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding