Tumor cells are well-known to have elevated levels of sialylated surface glycoproteins. The addition of sialic acid (a negatively-charged sugar) to select surface receptors modulates the structure and function of such receptors, leading to changes in intracellular signaling and gene expression. Increased tumor cell sialylation occurs, in part, through the upregulation of sialyltransferases such as ST6GAL1, an enzyme that adds an α2-6 linked sialic acid to N-glycosylated proteins. ST6GAL1 is overexpressed in numerous malignancies, including pancreatic ductal adenocarcinoma (PDAC), and high expression correlates with a poor prognosis. Prior work from our group revealed that ST6GAL1 confers a cancer stem cell phenotype, typified by invasiveness and apoptosis-resistance, through the sialylation-dependent activation of receptors such as EGFR. In the current investigation we used human Suit2 PDAC cells, as well as two metastatic Suit2 subclones, to show that ST6GAL1 activity promotes tumor progression and metastasis in tumor xenograft models. Moreover, high ST6GAL1 expression in this isogenic cell series induces EGFR activation and epithelial to mesenchymal transition. To complement tumor xenograft experiments, we developed a genetically-engineered mouse (GEM) model with conditional ST6GAL1 expression in the pancreas (termed, "SC" mice) and crossed this line to the "KC" PDAC model, which expresses oncogenic Kras (KrasG12D ) in the pancreas. Mice with dual expression of ST6GAL1 and KrasG12D ("KSC" mice) exhibit greatly accelerated PDAC initiation, progression, and mortality when compared with KC mice. In light of ST6GAL1's known role in conferring stem/progenitor properties, we hypothesized that ST6GAL1 activity contributes to PDAC initiation by fostering acinar to ductal metaplasia (ADM). During ADM, pancreatic acinar cells de-differentiate into ductal-like, progenitor cells and acquire greater proliferative potential as well as apoptosis resistance. Cells undergoing ADM are particularly vulnerable to oncogenic transformation. To interrogate whether ST6GAL1 promotes ADM, we compared SC mice with control, wild-type littermates. Using a variety of analyses and model systems including RNA-Seq of GEM pancreata, organoid lines derived from GEM pancreata, the canonical 266-6 ADM cell model, and in vivo model of inflammation-induced ADM, we determined that high expression of ST6GAL1 in acinar cells imparts an ADM-like phenotype, as evidenced by the upregulation of stem and ductal genes and downregulation of genes associated with differentiated acinar cells. Furthermore, GEM tissues and organoids with ectopic ST6GAL1 expression display strikingly elevated levels of activated EGFR. Given that activation of EGFR is one the major drivers of ADM, these data suggest a potential mechanism by which ST6GAL1-mediated sialylation facilitates ADM. Collectively these results point to a critical role for ST6GAL1 in both early and late stages of pancreatic malignancy.