# Glycosylation-dependent mechanisms regulating ovarian tumor cell phenotype

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $317,419

## Abstract

Project Summary/Abstract
 Aberrant surface glycosylation is a well-known tumor biomarker, however the functional role of the tumor
glycome in regulating tumor cell phenotype remains poorly-understood. α2-6 sialic acid (a bulky, negatively-
charged sugar) is a prominent tumor-associated glycan elaborated by the ST6Gal-I glycosyltransferase.
Research from our group has shown that ST6Gal-I sialylates select membrane receptors, including TNFR1,
which in turn causes activation of NF-κB. ST6Gal-I is pervasively upregulated in ovarian cancer (OC), and
high expression levels correlate with poor patient survival and metastasis. Furthermore, forced ST6Gal-I
overexpression in multiple animal models fosters tumor initiation and progression. The central hypothesis of
the current proposal is that ST6Gal-I activity contributes to OC development by promoting NF-kB-dependent
signaling events that confer cancer stem cell (CSC)-like features to tumor cells. The NF-kB axis is one of
the most hyperactivated pathways in CSCs, and is a well-accepted driver of the CSC phenotype. The
concept that NFkB signaling and CSC behavior are regulated by tumor cell sialylation advances a new
paradigm in cancer cell biology. The proposed research has two principal objectives. The first (Aim 1) is to
establish that the master stem cell transcription factor, Sox2, is a key inducer of ST6Gal-I upregulation in
OC. Our preliminary data show that Sox2 binds directly to the ST6Gal-I promoter to stimulate transcription.
Downstream of ST6Gal-I upregulation, we postulate that ST6Gal-I-mediated receptor sialylation directs
CSC reprogramming via NFkB, consequently facilitating tumor initiation. The second major goal of the
proposal (Aim 2) is to define ST6Gal-I’s role in OC peritoneal dissemination, which is one of the chief
contributors to patient mortality. Unlike most solid tumors, OC primarily disseminates via fluid flow
throughout the peritoneal cavity rather than transit through the vasculature or lymphatics. The peritoneum
has very low oxygen tension, and therefore OC cell adaptation to hypoxia is an essential element in OC
progression. Recent studies from our group have shown that ST6Gal-I activity facilitates protection against
hypoxia by potentiating HIF1α signaling. Aim 2 will test that premise that ST6Gal-I-mediated hypoxia
adaptation is critical for OC cell survival and expansion within the peritoneal tumor microenvironment.
Collectively, the proposed studies are expected to uncover a highly novel glycosylation-dependent
mechanism that plays seminal roles in both early and late stages of OC development and progression.

## Key facts

- **NIH application ID:** 9857567
- **Project number:** 5R01CA225177-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Susan L Bellis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $317,419
- **Award type:** 5
- **Project period:** 2014-05-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857567

## Citation

> US National Institutes of Health, RePORTER application 9857567, Glycosylation-dependent mechanisms regulating ovarian tumor cell phenotype (5R01CA225177-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9857567. Licensed CC0.

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