Impaired JNK signaling cooperates with KrasG12D expression to accelerate pancreatic ductal adenocarcinoma

Clare C Davies, Emma Harvey, Raymond F T McMahon, Katherine G Finegan, Frances Connor, Roger J Davis, David A Tuveson, Cathy Tournier

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)


The c-Jun N-terminal protein kinase (JNK) and its two direct activators, namely the mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) and MKK7, constitute a signaling node frequently mutated in human pancreatic ductal adenocarcinoma (PDAC). Here we demonstrate the cooperative interaction of endogenous expression of Kras(G12D) with loss-of-function mutations in mkk4 or both, mkk4 and mkk7 genes in the pancreas. More specifically, impaired JNK signaling in a subpopulation of Pdx1-expressing cells dramatically accelerated the appearance of Kras(G12D)-induced acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasias, which rapidly progressed to invasive PDAC within 10 weeks of age. Furthermore, inactivation of mkk4/mkk7 compromised acinar regeneration following acute inflammatory stress by locking damaged exocrine cells in a permanently de-differentiated state. Therefore, we propose that JNK signaling exerts its tumor suppressive function in the pancreas by antagonizing the metaplastic conversion of acinar cells toward a ductal fate capable of responding to oncogenic stimulation.

Original languageEnglish
Pages (from-to)3344-56
Number of pages13
JournalCancer Research
Issue number12
Publication statusPublished - 15 Jun 2014


  • Acinar Cells
  • Animals
  • Carcinogenesis
  • Carcinoma, Pancreatic Ductal
  • Cell Dedifferentiation
  • MAP Kinase Kinase 4
  • MAP Kinase Kinase 7
  • MAP Kinase Signaling System
  • Mice
  • Mice, Transgenic
  • Mutation, Missense
  • Pancreas
  • Pancreatic Neoplasms
  • Proto-Oncogene Proteins p21(ras)
  • Regeneration


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