Pancreatic Tumor Progression in the Absence of ADAM-mediated alpha-secretase Acti

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DESCRIPTION (provided by applicant): In the United States, only 4% of pancreatic ductal adenocarcinoma (PDAC) patients live 5- years past diagnosis, with most succumbing to the disease within 1 year. One of the reasons for the dismal outcome for these patients is the ineffectiveness of current chemotherapeutic agents. As we have come to understand the important biological mechanisms that initiate pancreatic tumorigenesis and its continued progression to cancer, it is clear that pancreatic tumors have reactivated signaling pathways that are largely silent in normal adult tissue but that are, instead, actively involved in pancreatic organ development and cellular differentiation. One such pathway that is apparently reactivated in PDAC is Notch. Notch activity is critical for maintaining an undifferentiated progenitor cell population in the pancreas during development and probably in the adult organ as well. In part, it is the continued existence of these rare adult progenitor cells that allows the pancreas to regenerate when damaged in diseases such as pancreatitis. However, by chronic reactivation of Notch, tumor cells take advantage of this ability to block differentiation, allowing them to continue to proliferate while ignoring the detrimental effects of active oncogenes and signals that would promote the differentiation of a normal progenitor cell. In an effort to target the Notch pathway in the pancreas, we have created conditional knockout animals for the genes encoding two proteins that have been shown to be critical for Notch activation: ADAM-10 (A Disintegrin And Metalloprotease-10) and ADAM-17. Using pancreas-specific knockouts of these genes, we propose a pilot study to examine 1) Tissue development and cellular differentiation, to better understand which ADAM controls Notch in these processes. 2) Tissue regeneration after cerulein-induced pancreatitis, to test the maintenance of an adult progenitor cell population as well as the effectiveness of these cells in healing the injured pancreas. 3) PDAC formation, by mating the ADAM knockout animals to the p48Cre-LSLKrasG12D mouse PDAC model, the most accurate animal model of human PDAC. Because of their role in Notch activation, as well as the activation of other signal transduction pathways that promote PDAC progression, these studies will test whether one or both of these ADAM proteases are promising novel therapeutic targets for treating PDAC patients. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of human cancer. One of the reasons for the dismal outcome of this disease is the ineffectiveness of current chemotherapy. For this pilot study, we have deleted the genes for two proteins, known as ADAM-10 and ADAM-17, specifically from the pancreas. These proteins have been shown to control multiple signals that promote PDAC. The results of this pilot study will help us test if ADAM-10 and ADAM-17 are appropriate targets for treating of PDAC patients.