Project Summary This project will elucidate a novel mechanism by which chronic pancreatitis leads to pancreatic adenocarcinoma, with a specific focus on one of the earliest neoplastic events, acinar to ductal metaplasia (ADM). We have identified a new enzyme, ST6Gal1, that is involved in both pancreatitis and pancreatic adenocarcinoma. ST6Gal1 is a membrane bound golgi sialyltransferase that adds sialic acid, in an α2-6 linkage, to N-glycosylated proteins that are destined for the plasma membrane. ST6Gal1 has been shown to endow cells with cancer stem cell (CSC)-like properties including greater tumor initiating potential and enhanced resistance to apoptosis through TNFR1/NFκB signaling axis. To study the role of ST6Gal1 in pancreatic cancer, we generated a transgenic mouse line with ST6Gal1 overexpression (ST6-OE) exclusively in the pancreas and crossed these mice to a pancreatic ductal adenocarcinoma (PDAC) mouse model (KC mice) to generate KC mice with ST6-OE in the pancreas (KC-ST6-OE mice). Compared to KC mice (median survival = 13.6 mo) KC-ST6-OE mice demonstrate accelerated mortality (median survival = 4.3 mo). The accelerated pathogenesis observed when ST6Gal1 expression is forced suggests that ST6Gal1 may prime the cells for transformation. These findings led us to examine if ST6Gal1 upregulation in premalignant cells can promote neoplasia. IHC analysis of human chronic pancreatitis tissue arrays demonstrated an increase in ST6Gal1 expression in ADM lesions and co-expression of the stem/ductal transcription factor, Sox9. Therefore, we hypothesize that during pancreatitis-induced inflammation, ST6Gal1 expression promotes acinar cell survival and thus primes the cell for transformation. To test this hypothesis, we ask the following: i) Does ST6Gal1 promote cell survival following inflammatory damage and promote ADM formation? ii) Given that STGal1 enhances both basal and TNF-dependent TNFR1/NFkB signaling, does ST6Gal1 imparts stem/ductal characteristics through activating a TNFR1-NFκB-Sox9 pathway? iii) Does ST6Gal1 prime cells for KRAS driven transformation (>90% of PDAC patients display KRAS mutation)? iv) Does ST6Gal1 promote the transition from ADM-lesions into Pancreatic intraepithelial neoplasias (PanINs)? The findings from this study may lead to the identification of biomarkers that report whether neoplastic transformation has occurred and lead to therapeutics that can delay or suppress this transition.