Discoidin Domain Receptors: Novel Players in Pancreatitis and Pancreatic Preneoplasia

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DESCRIPTION (provided by applicant): The goal of this R21 application is to pursue a novel area of investigation in pancreatic cancer development, and apply this knowledge for early disease detection and treatment. Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal form of cancer that is characterized by a strong fibrotic response, which promotes malignancy. Pancreatic inflammation (pancreatitis) and the ensuing fibrotic response cause the acinar cells to undergo a metaplastic event in which the acinar cells transdifferentiate into duct-like cells wih progenitor-like characteristics, a process known as Acinar-to-Ductal Metaplasia (ADM). Current concepts indicate that ADM constitute the early pathological lesion that eventually progresses into PDAC. ADM proceeds within the context of a pro-fibrotic collagen-rich matrix, which is a key feature of PDAC and chronic pancreatitis, a risk factor for PDAC development. Therefore, the interactions of the acinar cells with the underlying collagen matrix are likely to play a pivotal rle in the activation of the transdifferentiation programs that lead to ADM lesions and eventually to PDAC development. However, how acinar cells respond to the collagen matrix during formation of ADM lesions remains ill defined. New preliminary evidence suggests a role for the Discoidin Domain Receptors (DDRs), a unique set of receptor tyrosine kinases that signal in response to collagen and thus represent logical candidates for mediating the morphogenetic programs of acinar cells during ADM. However, the expression and functional contribution of DDRs in ADM formation and pancreatitis have not been investigated. Because DDRs mediate collagen-initiated signaling and, as RTKs, are amenable to drug intervention, we propose the novel hypothesis that DDRs mediate the reprograming of acinar cells within the collagen microenvironment that contribute to ADM formation during pancreatic injury and early neoplastic development. To test this hypothesis, we propose the two Specific Aims: 1) To investigate the contribution of DDRs to acinar-to-ductal metaplasia (ADM) in acinar explants, and 2) To investigate the expression and role of DDRs in pancreatitis. To accomplish these Aims we will utilize a variety of relevant in vitro and in vivo models that recapitulate the morphogenetic program of ADM including acinar explants and pancreatitis models, and exploit the availability of mice with genetic disruption of DDR expression and various tools to target DDR activity. We expect that the results of these novel studies will pave the way for a new scientific direction in PDAC research, which may lead to the development of new approaches in pancreatic cancer diagnosis and treatment. Hence, the studies proposed in this application are in line with the R21 goals to promote the early and conceptual stages of research efforts on novel scientific ideas that have the potential to substantially advance cancer research.