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.

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*
  • Transcription Factors / metabolism
  • ras Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • KRAS protein, human
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Tead2 protein, mouse
  • Transcription Factors
  • Yap protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins

Associated data

  • GEO/GSE53169