Impaired JNK signaling cooperates with KrasG12D expression to accelerate pancreatic ductal adenocarcinoma.
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.
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.
Clare C
CC
Davies
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.
Emma
E
Harvey
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.
Raymond F T
RF
McMahon
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.
Katherine G
KG
Finegan
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.
Frances
F
Connor
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.
Roger J
RJ
Davis
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.
David A
DA
Tuveson
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.
Cathy
C
Tournier
D061354:Acinar Cells / Q000201:enzymology; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism*; D054337:Cell Dedifferentiation; D048670:MAP Kinase Kinase 4 / Q000235:genetics* / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D010179:Pancreas / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D012038:Regeneration
D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)