This application proposes experiments that will further explore the molecular mechanisms by which the cell surface associated mucin, MUC1, contributes to the progression of pancreatic adenocarcinoma. Previous work has established that MUC1 is overexpressed and differentially glycosylated by different adenocarcinomas, and that this overexpression is associated with aggressive (invasive and metastatic) forms of pancreatic and other cancers. MUC1 plays multiple and key roles at the cell surface of epithelial cells: it configures some aspects of cell surface adhesion properties, and it communicates information about the status of the cell surface to the nucleus through participation in different pathways of signal transduction. We now know that alterations in MUC1 structure or binding status are communicated to internal compartments of the cell through modifications of the cytoplasmic tail, which can be phosphorylated by different serine, threonine and tyrosine kinases. Our recent results have revealed that MUC1 can have dramatic modulatory effects on cellular functions in response to external growth factor/cytokine stimulation through interactions with receptor tyrosine kinases. MUC1 overexpression on pancreatic tumor cells significantly increases the invasive and metastatic properties of cells stimulated with PDGF-BB. The mechanism whereby this occurs involves phosphorylation of the MUC1 cytoplasmic tail by PDGFR2 and subsequent signaling by the MUC1 cytoplasmic tail, which is transported to and modifies the transcriptional activity of specific promoter sites in the nucleus in association with other signaling and transcription factors. In contrast to the results with PDGF-BB, stimulation of pancreatic tumor cells with hepatocyte growth factor (HGF) under conditions of MUC1 overexpression decreases cell invasive through a mechanism in which MUC1 cytoplasmic tail phosphorylated by cMet associates with p53 and modulates the ability of p53 to associate with AP-1 at promoter sites and activate expression of genes associated with invasion (e.g. MMP1). These results support previous findings that MUC1 can influence the invasive and metastatic properties of tumors in different ways (both enhancing and decreasing). Our results provide a molecular explanation for these different effects by showing that they are context dependent and affected by the cytokine and tissue environment of the cell on which MUC1 is expressed. These results provide new insight into the overall metastatic process, in which cells first take on activities of invasion to leave a primary tumor site, which can be shut down when metastatic tumor cells take up residence in a new organ site and no longer need to migrate. As we go forward we have chosen to focus this renewal application on the mechanisms by which MUC1 is involved in signal transduction and transcriptional regulation, and how this influences invasion and metastasis of pancreatic tumor cells.
This application proposes experiments that will further explore the molecular mechanisms by which the cell surface associated mucin, MUC1, contributes to the progression of pancreatic adenocarcinoma. This renewal application will investigate the mechanisms by which MUC1 is involved in signal transduction and transcriptional regulation, and how this influences invasion and metastasis of pancreatic tumor cells.
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