ST6Gal1 Contributes to Pancreatic Cancer Initiation by Promoting Pancreatitis-Induced Acinar to Ductal Metaplasia

Aberrant glycosylation is one of the earliest known hallmarks of cancer. Amongst the predominate changes in tumor cell glycosylation is an increase in α2-6 sialylation on N-glycans, a modification elaborated by the ST6Gal1 sialyltransferase. ST6Gal1 activity dramatically alters cellular function via the sialylation of various surface receptors such as EGFR and TNFR1, resulting in altered signal transduction and gene expression. ST6Gal1 expression is upregulated in multiple cancers, including pancreatic ductal adenocarcinoma (PDAC). Recent studies from our group suggest that the upregulation of ST6Gal1 in pancreatic acinar cells may promote PDAC initiation by facilitating acinar to ductal metaplasia (ADM), a process in which acinar cells de-differentiate into ductal-like, progenitor cells. In the nonmalignant pancreas, ADM is induced primarily by pancreatitis, a known risk factor for PDAC. Pancreatitis causes acinar cell apoptosis, however some cells undergo ADM and acquire regenerative capabilities essential for tissue healing. Notably, ADM-like cells are particularly susceptible to oncogenic transformation. In the current study we determined that ST6Gal1 was strikingly upregulated in pancreatic tissues from chronic pancreatitis patients and mice with experimental pancreatitis. Furthermore, ST6Gal1 was selectively expressed in the ADM-like cells, as identified both morphologically and by staining for ADM-specific markers. ST6Gal1 activity was associated with a proliferative phenotype. More than 50% of cells with upregulated ST6Gal1 co-expressed the proliferative marker, Ki67, whereas activated caspase 8 was undetectable in ST6Gal1-positive cells. To interrogate a functional role for ST6Gal1 in ADM, we developed genetically-engineered mice with ST6Gal1 expression in the pancreas ("SC" mice). Importantly, acinar cells from SC mice exhibited ADM-like characteristics, indicated by increased expression of classic stem and ductal genes. RNASeq analyses comparing SC and WT pancreata indicated that SC cells had an enrichment in: stem cell pathways; a pancreatic ductal cell program; and gene networks associated with pancreatic cancer. Additionally, organoids derived from SC pancreata displayed increased expression of stem and ductal genes relative to WT organoids, as well as greater organoid-forming potential and growth. To evaluate inflammation-induced ADM, SC and WT mice were injected with cerulein to induce pancreatitis, and the ADM-like cells were quantified by examining surface ADM markers by flow cytometry. Following induction of pancreatitis, more ADM-like cells were present in SC versus WT pancreata. Finally, we crossbred SC mice to the "KC" PDAC model, which expresses oncogenic KRas (KrasG12D ) in the pancreas. Mice with dual expression of ST6Gal1 and KrasG12D had greatly accelerated PDAC initiation, progression and mortality as compared with KC mice. Together these data suggest that the upregulation of ST6Gal1 during chronic pancreatitis may prime acinar cells for neoplastic transformation by facilitating ADM. © FASEB.