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 CC, Harvey E, McMahon RF, Finegan KG, Connor F, Davis RJ, Tuveson DA, Tournier C. (2014). Impaired JNK signaling cooperates with KrasG12D expression to accelerate pancreatic ductal adenocarcinoma. Davis Lab Publications. https://doi.org/10.1158/0008-5472.CAN-13-2941. Retrieved from https://escholarship.umassmed.edu/davis/50