Tumor glycans in pancreatic cancer development, progression and immune suppression 

Seminar Details

Host: Dr. Vlad Panin

Time: 4:00-5:00pm

Location: BICH Rm 108

Seminar Abstract

Aberrant glycosylation, including increased surface sialylation, is a hallmark feature of cancer cells. The addition of sialic acid (a negatively-charged sugar) to membrane receptors modulates the structure and function of such receptors, leading to changes in intracellular signaling and gene expression. Elevated tumor cell sialylation occurs, in part, through the upregulation of sialyltransferases such as ST6GAL1. 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 pivotal role in promoting PDAC initiation and progression in multiple murine models. For example, we engineered mice with pancreas-specific expression of transgenic ST6GAL1 in combination with the KRasG12D oncogene. Compared with mice expressing KRasG12D alone, mice with dual expression of ST6GAL1 and KRasG12D displayed greatly accelerated rates of PDAC onset, metastatic progression and mortality. Mechanistically, ST6GAL1 contributed to PDAC initiation by facilitating a process known as acinar to ductal metaplasia (ADM). During ADM, acinar cells de-differentiate into ductal, progenitor-like cells which are particularly vulnerable to KRas-driven oncogenesis. ST6GAL1 fostered ADM via the sialylation of receptors such as EGFR. In tandem with its tumor-autonomous functions, ST6GAL1 promoted PDAC progression by inducing immune suppression. Specifically, sialylated glycans generated by ST6GAL1 were found to serve as ligands for select members of the Siglec family of immune checkpoint proteins. The engagement of sialic acids with Siglecs 3,9 and 10 on macrophages stimulated macrophage polarization into an M2-like, tumor-supportive phenotype. Collectively, these results highlight a critical role for tumor cell sialylation in driving PDAC development, progression and immune suppression.