Pancreatic adenocarcinomas are among the most fatal cancers because of their extensive invasion intosurrounding tissues and metastasis to distant organs, even at an early stage of tumor progression. The poorprognosis of this malignancy also reflects a generally poor response to current therapies. Thus, a basicunderstanding of the biology of these tumors and the mechanisms that promote their invasion andmetastasis will provide a basis for developing new methods for diagnosis and treatment.Pancreatic adenocarcinomas are characterized by extensive deposition of extracellular matrix, which canhave profound effects on cell behavior. We have preliminary studies showing that cells derived frompancreatic adenocarcinomas respond in vitro to exogenous collagen type I by undergoing a transformationFrom a non-motile epithelial cell to a highly motile and invasive mesenchymal cell. A hallmark of epithelial tomesenchymal transitions is increased expression of N-cadherin, a protein we and others have shownpromotes tumor cell invasion. Of particular significance to the current proposal, N-cadherin is expressed bymore than 50% of invasive pancreatic tumors.Recent studies have shown that the N-cadherin antagonist, Exherin , developed by Adherex Technologies,Inc. Durham, NC, inhibits the activity of N-cadherin in vitro and in vivo. We hypothesize that Exherin iscapable of inhibiting N-cadherin-induced motility in tumor cells, and propose to test this hypothesis in Ncadherin-expressing pancreatic cancer cells in a tissue culture model of cell motility, and in a mouse modelof invasive pancreatic cancer. In addition, we propose to characterize the signaling pathways downstream ofcollagen I that promote up-regulation of N-cadherin and invasion, for the purpose of identifying potentialinhibitors that could be used in combination therapy with Exherin . Finally, we will test the efficacy ofExherin as a treatment for human pancreatic cancer in clinical trials.
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