Abstract 336: Role of ST6GAL1 sialyltransferase in early stages of pancreatic cancer development

Abstract

Abstract Increased cell surface sialylation is a prevalent feature of tumor cells. The addition of sialic acid (a negatively-charged sugar) to select surface receptors modulates the structure and function of these 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. Our group has shown that ST6GAL1 plays a causal role in promoting PDAC initiation and progression in tumor xenograft and genetically-engineered mouse (GEM) models. As one example, we developed a GEM model with conditional ST6GAL1 expression in the pancreas and crossed this line to the “KC” PDAC model, which expresses oncogenic Kras (KrasG12D). 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 progenitor-like cell characteristics, we postulated 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 Kras-dependent transformation. Using a variety of approaches and model systems including GEM organoids, 3D acinar cultures, acinar-like cell lines, and an in vivo assay for ADM, we uncovered a novel function for ST6GAL1 in promoting ADM. We further determined that high ST6GAL1 activity in acinar cells cooperates with KrasG12D to drive neoplasia. Finally, our studies suggest that the tumor-promoting effects of ST6GAL1 are mediated, at least in part, by ST6GAL1-mediated sialylation of EGFR. These collective results highlight a novel glycosylation-dependent mechanism involved in early stages of PDAC development. Citation Format: Susan L. Bellis, Asmi Chakraborty, Nikita Bhalerao, Michael Marciel, Jihye Hwang, Austin Silva. Role of ST6GAL1 sialyltransferase in early stages of pancreatic cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 336.