The trans differentiation of pancreatic acinar cells to a duct-like, pluripotent progenitor cell type (ADM, acinar-to- ductal metaplasia) is an initial step leading to the development of pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer. ADM can be initiated after activation of the epidermal growth factor receptor, acquisition of activating mutations of Kras and macrophage-secreted cytokines. However, the common signaling mechanism driving ADM downstream of these inducers are largely unknown. It is our hypothesis that activation of a PKD1 signaling is a common feature of inducers of acinar-to-ductal metaplasia, driving the formation of PanINs and the progression to pancreatic tumors. To test this we will: Determine if activation of PKD1 is a common mechanism for different inducers of ADM (Specific Aim 1); identify PKD1 downstream signaling pathways that drive ADM and the formation of duct-like pancreatic progenitor cells (Specific Aim 2); determine if expression and/or activity of PKD1 indicate progression of ADM to PanINs and PDA in vivo (Specific Aim 3); and use genetic animal models to define the role of PKD1 in development of pancreatic cancer (Specific Aim 4). Successful completion of our project will identify PKD1 as a common feature of processes that initiate the development of pancreatic cancer. It also will define the signaling events up- and downstream of PKD1 that facilitate PanIN formation and contribute to development of pancreatic cancer. Early diagnosis and early targeting are key for successful intervention of pancreatic cancer. Our results will provide the basis for both, since PKD1 is a targetable kinase and can be a molecular signaling marker for early events.

Public Health Relevance

In this grant application we will investigate the mechanisms of how protein kinase D1 (PKD1) contributes to the initiation of pancreatic cancer. Our overall goals are to understand PKD1-mediated signaling mechanisms driving cancer initiation and to determine if they can be predictive markers for development or targets for prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA200572-05
Application #
9831050
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Yassin, Rihab R
Project Start
2015-12-01
Project End
2021-05-31
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Storz, Peter (2018) Protein kinase D1: gatekeeper of the epithelial phenotype and key regulator of cancer metastasis? Br J Cancer 118:459-461
Fleming, Alicia K; Storz, Peter (2017) Protein kinase C isoforms in the normal pancreas and in pancreatic disease. Cell Signal 40:1-9
Durand, Nisha; Storz, Peter (2017) Targeting reactive oxygen species in development and progression of pancreatic cancer. Expert Rev Anticancer Ther 17:19-31
Döppler, Heike; Storz, Peter (2017) Mitochondrial and Oxidative Stress-Mediated Activation of Protein Kinase D1 and Its Importance in Pancreatic Cancer. Front Oncol 7:41
Storz, Peter (2017) Acinar cell plasticity and development of pancreatic ductal adenocarcinoma. Nat Rev Gastroenterol Hepatol 14:296-304
Cobbaut, Mathias; Derua, Rita; Döppler, Heike et al. (2017) Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop. Sci Rep 7:887
Storz, Peter (2017) KRas, ROS and the initiation of pancreatic cancer. Small GTPases 8:38-42
Ding, Li; Liou, Geou-Yarh; Schmitt, Daniel M et al. (2017) Glycogen synthase kinase-3? ablation limits pancreatitis-induced acinar-to-ductal metaplasia. J Pathol 243:65-77
Liou, Geou-Yarh; Bastea, Ligia; Fleming, Alicia et al. (2017) The Presence of Interleukin-13 at Pancreatic ADM/PanIN Lesions Alters Macrophage Populations and Mediates Pancreatic Tumorigenesis. Cell Rep 19:1322-1333
Durand, Nisha; Bastea, Ligia I; Döppler, Heike et al. (2017) Src-mediated tyrosine phosphorylation of Protein Kinase D2 at focal adhesions regulates cell adhesion. Sci Rep 7:9524

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