The role of MUC1 and its ligand myelin-associated glycoprotein in pancreatic cancer perineural invasion

MUC1 is a type-I transmembrane glycoprotein expressed by ductal epithelia in many organs, including the pancreas. In pancreatic adenocarcinoma, MUC1 is overexpressed and differentially glycosylated compared to normal epithelia. Preliminary data suggested that the siglec Myelin-Associated Glycoprotein (MAG), an adhesion molecule expressed on Schwann cells, may be a potential ligand for MUC1. Perineural invasion (PNI) in pancreatic adenocarcinoma is a common pathological phenomenon whereby cancer cells invade to become invested in the endoneurium of pancreatic nerves. Studies performed within the first section of this dissertation investigated the contribution of MUC1 and MAG to heterotypic adhesion between pancreatic tumor cells and Schwann cells in PNI. These studies demonstrated that increased expression of MUC1 or MAG enhanced adhesion between the cells. Conversely, specific inhibition of MAG or MUC1 glycans partially blocked adhesion. Furthermore, immunohistochemical analysis of pancreatic nerves and perineural invasion demonstrated that both MUC1 and MAG are expressed in these lesions.; MUC1 influences morphogenetic signal transduction via its cytoplasmic tail. MUC1 can localize to the nucleus where it interacts with and affects many transcription factors. Studies performed within the second section of this dissertation investigated whether binding of MAG to MUC1 induced a signal in the cytoplasmic tail. These studies demonstrated that treatment of pancreatic tumor cells with MAG produced no detectable change in the MUC1 cytoplasmic localization or the transcriptional profile.; Additionally, MUC1 can influence metastasis in cancer cells via signal transduction through its cytoplasmic tail, possibly by localizing to the nucleus. Preliminary data of a mutant form of MUC1, in which its extra-cellular tyrosines were mutated to phenylalamne, suggested that its cytoplasmic tail was localized primarily in the nucleus while its extracellular domain was secreted. Studies performed within the third section of this dissertation investigated whether the nuclear and secreted mutant model of MUC1 could affect the metastatic and transcriptional potential of pancreatic tumor cells. These studies demonstrated that this model of MUC1 did not alter the metastatic potential of cells. Furthermore, additional studies proved that this mutant form of MUC1 only faithfully recapitulated a model of secreted MUC1 but was not a model of nuclear MUC1.