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Cancer Res. 2014 Jun 15;74(12):3344-56. doi: 10.1158/0008-5472.CAN-13-2941. Epub 2014 Apr 8.

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

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1
Authors' Affiliations: Faculty of Life Sciences and Department of Histopathology Medical School, University of Manchester, Manchester; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom; and Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts cathy.tournier@manchester.ac.uk c.c.davies@bham.ac.uk.
2
Authors' Affiliations: Faculty of Life Sciences and Department of Histopathology Medical School, University of Manchester, Manchester; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom; and Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.

Abstract

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.

PMID:
24713432
PMCID:
PMC4058314
DOI:
10.1158/0008-5472.CAN-13-2941
[Indexed for MEDLINE]
Free PMC Article
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