Original ResearchFull Report: Basic and Translational—PancreasMAPK Signaling Is Required for Dedifferentiation of Acinar Cells and Development of Pancreatic Intraepithelial Neoplasia in Mice
Section snippets
Mice
Mice were housed in specific pathogen-free facilities at the University of Michigan Comprehensive Cancer Center. This study was approved by the University of Michigan's University Committee on Use and Care of Animals. p48Cre (Ptf1aCre) mice16 were intercrossed with TetO-KrasG12D17 (expressing the murine mutant form Kras4BG12D) and Rosa26rtTa-IRES-EGFP18 to generate p48Cre; TetO-KrasG12D; Rosa26rtTa-IRES-EGFP (iKras*) mice. LSL-KrasG12D mice were bred with p48Cre mice to create KC mice.
Up-Regulation of the MAPK Pathway After Acute Pancreatitis
We first investigated the activation of the MAPK pathway after the induction of acute pancreatitis in 2 genetically engineered mouse models of pancreatic cancer expressing oncogenic Kras*: iKras*, KC, and littermate controls. Although both models have pancreas-specific expression of Kras*, in iKras* mice the expression can be induced at will,4 whereas in KC mice the expression begins during embryonic development.6 Control, iKras*, and KC mice (n = 3–4/genotype) were 4–6 weeks old, an age when
Discussion
We previously showed that oncogenic Kras* is required throughout pancreatic carcinogenesis, from precursor lesions to metastatic tumors.4, 36 Among downstream effectors of Kras, the MAPK and phosphatidylinositol-3 kinase (PI3K) pathways have been implicated in pancreatic cancer progression; however, the relative importance of these 2 pathways during different stages of pancreatic carcinogenesis is still a matter of debate.37, 38 This question is highly clinically relevant because inhibitors to
Acknowledgments
The authors thank Dr Yaqing Zhang, Esha Mathew, Arthur L. Brannon III, and Kevin T. Kane for scientific discussion and reading of the manuscript; Marsha Thomas for laboratory support; and Dr Yaqing Zhang for help with tissue pathology and quantification. The p48-Cre mouse and Pdx1 antibody were generous gifts from Dr Chris Wright (Vanderbilt University), the Mist1 antibody was generously provided by Dr Stephen Konieczny (Purdue University), and the Hes1 antibody was a generous gift from Dr Ben
References (44)
- et al.
Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia
Gastroenterology
(2012) - et al.
Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Cell
(2012) - et al.
Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse
Cancer Cell
(2003) - et al.
Molecular analysis to detect pancreatic ductal adenocarcinoma in high-risk groups
Gastroenterology
(2005) - et al.
Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence
Cancer Cell
(2011) - et al.
Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma
Cancer Cell
(2012) - et al.
Control of cell identity in pancreas development and regeneration
Gastroenterology
(2013) - et al.
Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma
Gastroenterology
(2013) - et al.
Induced Mist1 expression promotes remodeling of mouse pancreatic acinar cells
Gastroenterology
(2012) - et al.
Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia
Gastroenterology
(2009)
Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer
Cancer Cell
EGF receptor is required for KRAS-induced pancreatic tumorigenesis
Cancer Cell
Core signaling pathways in human pancreatic cancers revealed by global genomic analyses
Science
Development of farnesyl transferase inhibitors: a review
Oncologist
Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice
J Clin Invest
MAP kinase signalling pathways in cancer
Oncogene
K-RAS mutation in the screening, prognosis and treatment of cancer
Biomark Med
Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group
N Engl J Med
Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice
J Clin Invest
Cholecystokinin rapidly activates mitogen-activated protein kinase in rat pancreatic acini
Am J Physiol
Activation of MAP kinase kinase (MEK) and Ras by cholecystokinin in rat pancreatic acini
Am J Physiol
Effects of mitogen-activated protein kinase signaling pathway inhibition on the development of cerulein-induced acute pancreatitis in mice
Pancreas
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Author names in bold designate shared co-first authorship.
Conflicts of interest The authors disclose no conflicts.
Funding This project was supported by the University of Michigan Biological Scholar Program, the University of Michigan Comprehensive Cancer Center, Gastrointestinal Specialized Program of Research Excellence (GI-SPORE) P50CA13810 and NCI-1R01CA151588-01, a University of Michigan Program in Cellular and Molecular Biology training grant ( National Institutes of Health T32 GM07315), and by a University of Michigan Center for Organogenesis training grant (5-T32-HD007515) (M.A.C.), and also was supported by NCI R01 CA155198-02 (J.S.S.L.). The sponsors had no role in the study design.