Pancreatic Ductal Adenocarcinoma (PDA) is an aggressive and lethal cancer characterized by a collagen- dense microenvironment. The overproduction of collagen and the subsequent fibrosis that follows has been studied in recent years; however, the impact of this prominent feature in PDA is left inconclusive. Extended pancreatic injury, as seen in chronic inflammation (pancreatitis), results in a pro-fibrotic collagen-rich response that promotes an initial process called acinar-ductal metaplasia (ADM). ADM is an event in which the epithelial acinar cells transdifferentiate into duct-like cells with progenitor characteristics and is thought to be a precursor to PDA in the presence of oncogenic Kras. Therefore, investigating the interactions between the acinar cells with the collagen-dense stromal compartment may offer a point of intervention in the activation of ADM and the gradual development of PDA. New preliminary evidence suggests Discoidin Domain Receptor 2 (DDR2), a unique receptor tyrosine kinase (RTK) that signals in response to binding to its collagen ligand may play a role in the development of PDA. To date, the activation of DDR2 and the subsequent intracellular signaling that follows has not been studied in the context of pancreatic diseases. DDR2 is a probable candidate in the study of PDA due to the dominant collagen overproduction and its nature as an RTK that is amenable to drug intervention. With these facts in place, this proposal will test the hypothesis that DDR2 activation is necessary to promote signaling between tumor cells and stroma that is required for the progression and metastasis of PDA The following specific aims will: 1.) Test the hypothesis that DDR2 in tumor cells is required for the development of PDA. 2.) Test the hypothesis that DDR2 activation in tumor cells and fibroblasts is required for the invasion and metastasis of PDA. To accomplish these specific aims, human cell lines and genetically engineered mouse models will be used to perform the appropriate in vitro and in vivo experiments to study PDA progression and metastasis. The results from these innovative studies will establish the role of DDR2 in the progression of PDA with the overall future aim of identifying DDR2 as a diagnostic and therapeutic target for patients. The proposed studies in this application follow the objectives of the Ruth L. Kirschstein National Research Service Award (NRSA) for Individual Predoctoral Fellowship (Parent F31) in determining novel methods and generating scientific ideas to promote the advancement of cancer research.
Pancreatic Ductal Adenocarcinoma (PDA) is one of the most lethal and clinically challenging cancers that will affect over 50,000 adults this year with a 5-year survival rate at a dismal 8%. The aims of this application will focus on studying Discoidin Domain Receptor 2 (DDR2) as a point of mediation between pancreatic cancer cells and the collagen-dense microenvironment presented throughout several stages in the development of PDA. The achievement of this proposal will determine the contribution of DDR2 as a potential diagnostic and therapeutic target for this devastating disease.
