Like many epithelial tumors, pancreatic adenocarcinomas develop in an abnormal fibrotic microenvironment. While this environment is thought to contribute to tumor invasion, recent experiments have shown that it also contributes to early development of epithelial tumors. We have established a novel transgenic mouse model that develops pancreatic fibrosis followed by hyperplastic ductal lesions that grow into the fibrotic regions. These lesions are thought to be precursors to pancreatic adenocarcinoma. The transgenic mice we have developed have a 3-fold elevation in a normally expressed growth factor, HB-EGF. Thus, a slight imbalance in a normally produced growth factor is able to induce pancreatic fibrosis and ductal hyperplasia. We have begun to dissect the molecular mechanisms underlying this disease progression by isolating different tissues from wildtype and HB-EGF-overexpressing pancreata and recombining them in ex vivo culture. Recombining HB-EGF overexpressing tissue with normal stellate cells, the cells that give rise to fibrosis, activates these cells, reproducing early steps in fibrogenesis. Using our in vivo mouse model combined with ex vivo co-culture experiments, we propose to elucidate the role of the HB-EGF receptor, EGFR, in fibrogenesis and ductal hyperplasia and in the activation of pancreatic stellate cells by using genetically modified mice that have reduced EGFR activity and by using pharmacological inhibitors of EGFR and its downstream effectors. We will also elucidate the type of signaling produced by HB-EGF, juxtacrine, paracrine, or autocrine by testing the role of transmembrane and soluble HB-EGF in disease induction and by examining which cell type responds directly to HB-EGF in the induction of EGFR signaling. The proposed experiments will further our knowledge of the regulation and intracellular processes of pancreatic fibrogenesis and the role that fibrosis, combined with sustained HB-EGF signaling, has on epithelial hyperplasia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098322-02
Application #
6861716
Study Section
Special Emphasis Panel (ZRG1-GMA-3 (01))
Program Officer
Ault, Grace S
Project Start
2004-03-01
Project End
2008-02-29
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
2
Fiscal Year
2005
Total Cost
$247,640
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Ray, Kevin C; Blaine, Stacy A; Washington, M Kay et al. (2009) Transmembrane and soluble isoforms of heparin-binding epidermal growth factor-like growth factor regulate distinct processes in the pancreas. Gastroenterology 137:1785-94
Means, Anna L; Meszoely, Ingrid M; Suzuki, Kazufumi et al. (2005) Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development 132:3767-76