Impaired JNK signaling cooperates with KrasG12D expression to accelerate pancreatic ductal adenocarcinoma
Program in Molecular Medicine
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
Biochemistry | Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
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.
DOI of Published Version
Cancer Res. 2014 Jun 15;74(12):3344-56. doi: 10.1158/0008-5472.CAN-13-2941. Epub 2014 Apr 8. Link to article on publisher's site
Davies, Clare C.; Harvey, Emma; McMahon, Raymond F. T.; Finegan, Katherine G.; Connor, Frances; Davis, Roger J.; Tuveson, David A.; and Tournier, Cathy, "Impaired JNK signaling cooperates with KrasG12D expression to accelerate pancreatic ductal adenocarcinoma" (2014). Davis Lab Publications. 50.