The goal of the proposed study is to investigate the role of two embryonic signaling pathways, Hedgehog and Wnt, during the formation and growth of pancreatic adenocarcinoma. Pancreatic adenocarcinoma constitutes a devastating disease that is marked by a poor prognosis due to late detection, aggressive nature, and early metastasis of transformed cells. The proposed studies are designed to test whether ectopic activation of Hedgehog and Wnt signaling can activate tumor formation and if inhibition of these pathways induces tumor regression. We hypothesize that deregulation of either pathway is sufficient to induce tumorigenesis in pancreatic tissue and that their continued activities are required for tumor survival. Our general approach is to use a combination of cell culture assays and transgenic mouse experiments to deregulate the activity levels of both pathways in normal and transformed pancreatic cells. The first specific aim is to determine if uncontrolled Hedgehog signaling is one of the earliest events during formation of pancreatic adenocarcinoma. We propose to establish cell culture and in vivo model systems to study the formation of pancreatic cancer. The second specific aim is to determine if inhibition of Wnt signaling is sufficient to block proliferation and cause apoptosis in pancreatic adenocarcinoma cells. We will also test if ectopic activation of Wnt signaling in cultured pancreatic duct cells, as well as in mature pancreatic tissue in vivo, induces adenocarcinoma formation. The third specific aim is to determine if the Hedgehog and Wnt signaling pathways regulate each other's activities and whether growth and survival of pancreatic cancer cells depends on their cooperative functions. In summary, we will explore if deregulation of embryonic signaling pathways is implicated in the development and survival of pancreatic adenocarcinoma. We anticipate that these studies will improve our understanding of the molecular causes of this cancer. In the best case, they will help to design new strategies for treatment of human patients suffering from this disease.
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