Pancreatic cancer is the 5th most common cause of cancer-related death in the United States, partly due to difficulties with early detection and partly due to its resistance to conventional cancer therapies. As such, an initiative has been put forth in the Program Research Group Report: """"""""Pancreatic Cancer: An Agenda for Action"""""""" to encourage study of pancreatic tumor biology and reliable methods for detection and treatment. With this in mind, we have begun to explore some of the fundamental tumor biology of pancreatic cancer, focusing on the function and expression of matrix metalloproteinase-7 (MMP-7). It is known that epithelial metaplasia in the context of chronic pancreatitis (CP) increases the risk for pancreatic ductal adenocarcinoma (PDAC) by 16-50 fold. Matrix metalloproteinase-7 (MMP-7) is expressed in metaplastic duct-like epithelium in 93% and 100% of chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC) samples, respectively, and in tumor cells in 98% of PDAC samples. This striking association between MMP- 7 and pancreatic disease has led to the discovery that CP is severely inhibited in MMP-7 null mice, including an almost complete abrogation of ductal metaplasia. In this application, we propose to test the overall hypothesis that MMP-7 and proteins that regulate its expression are both necessary and sufficient to induce pancreatic ductal metaplasia, contributing to PDAC initiation and progression. Specifically, we will test if MMP-7 activity is necessary and sufficient for ductal metaplasia both in vitro. We will also analyze if MMP-7 function is necessary for PDAC formation, progression and invasion in mouse PDAC models. Finally, we will study the activity of two putative activators of MMP-7 expression, the pancreatic/duodenal homeobox protein (Pdx-1) and the AP-1 factor c-Jun, to study their ability to regulate MMP-7 and alter tumor cell behavior in immortal pancreatic duct cells and in human PDAC cell lines. We will also examine the role of Pdx-1 in regulating MMP-7 expression in mouse models of metaplasia in vivo. Overall, we expect these studies to contribute significantly to our knowledge of pancreatic tumor biology with immediate implications with regards to detection and treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA100126-01A1
Application #
6725194
Study Section
Special Emphasis Panel (ZRG1-GMA-3 (01))
Program Officer
Ault, Grace S
Project Start
2004-03-01
Project End
2009-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
1
Fiscal Year
2004
Total Cost
$246,820
Indirect Cost
Name
State University New York Stony Brook
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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