Abstract Altered surface glycosylation was one of the earliest known hallmarks of a tumor cell, however mechanistic insight into the role of glycans in regulating tumor cell phenotype remains limited. Among the subset of glycosyltransferases dysregulated in tumor cells, ST6Gal-I stands out as being consistently upregulated in a variety of different cancers. ST6Gal-I is a Golgi sialyltransferase that adds an a2-6-linked sialic acid, a negatively-charged sugar, to a select group of membrane receptors. Our work has focused on defining ST6Gal-I substrates and elucidating the function of these aberrantly-sialylated receptors in promoting aggressive tumor cell behaviors. Our prior studies showed that ST6Gal-I-directed receptor sialylation enhances ovarian tumor cell invasiveness, and also prevents tumor cell death induced by key apoptotic mediators including galectins, chemotherapy drugs (cisplatin), and certain death receptor activators. In new unpublished studies we find a novel role for ST6Gal-I in controlling downstream signaling from two death receptors, TNFR1 and Fas. Sialylation of Fas and TNFR1 by ST6Gal-I prevents ligand-induced internalization of these receptors, an event essential for apoptotic signaling. However, sialylation of TNFR1 and Fas does not simply shut off receptor activity, but instead diverts signaling toward survival pathways mediated by NFkB and MAPKs. This switch occurs as a consequence of sialylation-dependent retention of TNFR1 and Fas at the cell surface. Given that the ligands for TNFR1 and Fas (TNFa and FasL, respectively) are expressed predominantly by immune cells, we hypothesized that ST6Gal-I sialylation of these receptors may facilitate tumor cell survival within an inflammatory milieu, contributing to escape from immune surveillance. Modeling the tumor microenvironment, we exposed ovarian cancer cells either lacking or overexpressing ST6Gal-I to peritoneal ascites fluid harvested from ovarian cancer patients. Ascites is rich in cytokines including TNFa, sFasL and galectins. Forced expression of ST6Gal-I in ovarian cancer cells conferred protection against ascites-induced cell death, implicating a role for receptor sialylation in tumor cell survival during transcoelomic metastasis. In other unpublished studies, we conducted the first immunohistochemical analyses of ST6Gal-I expression in ovarian cancer, and determined that ST6Gal-I is upregulated in the majority of tumor specimens, including papillary serous and endometrioid carcinomas. Prior to our work, ST6Gal-I had only been measured at the mRNA level in ovarian cancer due to a lack of effective antibodies. To better understand ST6Gal-I's influence on tumor cell phenotype, RNA sequencing/Ingenuity Pathway Analyses were performed in ovarian cancer cells with forced ST6Gal-I overexpression, and it was shown that ST6Gal-I upregulation induced activation of pathways associated with cancer stem cells, including the Wnt signaling axis. These results are consistent with our prior studies in colon tumor cells indicating that ST6Gal-I expression is particularly high in cancer stem cells. Taken together, our results suggest that upregulation of ST6Gal-I in ovarian carcinoma leads to abnormal hypersialylation of a select group of receptors, in turn conferring an invasive, apoptosis-resistant, and chemoresistant tumor cell phenotype. Citation Format: Matthew J. Schultz, Zhongyu Liu, Charles N. Landen, Susan L. Bellis. Control of tumor cell survival mechanisms by a novel glycan-modifying enzyme. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A78.