Pancreatic cancer is a devastating disease with an exceptionally poor prognosis. Tumors of ductular origin comprise 95% of pancreatic neoplasms and have strong tendencies to invade surrounding parenchyma and metastasize to distal organs. Currently, the molecular mechanisms that support these critical processes are poorly defined. It is known that the actin cytoskeleton plays an important role and responds dynamically to stimulation by a family of Receptor Tyrosine Kinases (RTKs) that are upregulated significantly in many pancreatic tumors. This is a proposal to study the mechanisms by which RTKs activate dramatic reorganization of the actin cytoskeleton, which alters cell polarity and leads to cell migration, invasion, and metastasis. We have identified a key regulatory cytoskeletal complex in these cells composed of;a large mechanochemical GTPase called dynamin (Dyn2) that is markedly upregulated in human pancreatic tumors, the actin crosslinking protein cortactin, and the transforming kinase Src, which is activated by RTKs and binds and phosphorylates both Dyn2 and cortactin. Importantly, we have shown that this complex associates with the actin cytoskeleton, cellular membranes, as well as known oncogenic proteins implicated in pancreatic cancer to form "signaling platforms" that support the invasive process. Our recent manuscripts and unpublished observations provide strong support for the CENTRAL HYPOTHESIS of this study: mainly, the Dyn2-Cort-Src complex, in concert with the oncogenic proteins ?-actinin and Rac, is activated by elevated RTK cascades to mediate actin-plasma membrane dynamics that promote invasion and metastasis of neoplastic pancreatic ductular cells. This proposal will utilize state-of-the-art optical and molecular methods applied to pancreatic tumor cell lines, tissue micro-array (TMA) technology of human tumor samples, and in vivo animal models to define the molecular mechanisms by which this protein complex potentiates pancreatic neoplasia and metastasis. This proposal is organized into three distinct but related specific aims that will define the following; first, how these signaling platforms mediate large-scale internalization of RTKs from the cell surface to alter cell signaling cascades;second, how the Dyn2-Cort-Src complex mediates major actin reorganization in tumor cells that become migratory and invasive;and third, how tumor cell adhesion complexes form and proliferate to mediate degradation of the surrounding extracellular matrix to facilitate metastasis. This study will make close correlations between isolated cells and human tumors to provide novel information toward understanding the molecular mechanisms that make pancreatic tumors so aggressive, migratory, and lethal. In addition, it describes pre-clinical trials using novel, recently identified pharmacological inhibitors.
Pancreatic cancers are particularly lethal due to the aggressive way they spread and metastasize. This proposal will define some of the central mechanisms by which these tumor cells move away from the pancreas to invade peripheral organs by focusing on specific ongogenic proteins that are markedly upregulated in these cancers.
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