# A novel, transferable sialylation-mediated mechanism of chemoradioresistance in GI cancer

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $414,655

## Abstract

ABSTRACT — Combination chemoradiation is utilized to treat multiple gastrointestinal (GI) cancers including
rectal cancer. Rectal cancer affects 40,000 people per year in the US. Approximately 85% of patients have an
incomplete or poor response to treatment increasing their risk of recurrence. We have found that poor responders
harbor sub-clones that are more resistant to treatment, and that the enzyme ST6Gal-1 is enriched in these sub-
clones. ST6Gal-1 is a Golgi glycosyltransferase that adds the negatively-charged sugar, sialic acid (SA), to
specific proteins destined for the cell surface. SA can have profound effects on the structure and function of
proteins. ST6Gal-1 is one of the most pervasively upregulated glycosyltransferases in cancer cells. ST6Gal-1
has been shown to specifically promote tumor cell survival and resistance via sialylation. In addition, ST6Gal-1
has been found in extracellular vesicles (ECVs) made by cancer cells. ECVs are particles with a lipid membrane
that contains RNA and protein cargo; thus, they are potential mediators of transferable resistance between
cancer sub-clones. The role of ST6Gal-1 and ECVs in resistance to chemoradiation has not been investigated.
The overall objective of this application is to ascertain the role of ST6Gal-1 in innate and transferable resistance
to chemoradiotherapy in rectal cancer. Based on our preliminary data, we hypothesize that ST6Gal-1 mediates
resistance to chemoradiation in individual sub-clones in rectal cancer, that this resistance is transferred
to other sub-clones via ECVs spreading resistance, and that this resistance is regulated by ST6Gal-1
cleavage by BACE1. We have found that ST6Gal-1 is increased in rectal cancer models after treatment with
chemoradiation. We will investigate our hypothesis with 3 aims: AIM 1 — Determine the role of ST6Gal-1 in
chemoradiation resistance in human rectal cancer. We hypothesize that ST6Gal-1 causes treatment
resistance after chemoradiation by inhibiting apoptosis. We will employ cell sorting, sequencing, and shRNA
approaches. We will also conduct studies to investigate its function in patient samples. AIM 2 — Determine if
ECVs carrying ST6Gal-1 transfer resistance to chemoradiation between sub-clones in rectal cancer. We
hypothesize that ECVs act as vectors that impart resistance to chemoradiotherapy from sub-clone to sub-clone
by trafficking ST6Gal-1, and thus, glycoprotein sialylation, in rectal cancer causing decreased apoptosis in the
recipient sub-clones. AIM 3 — Determine if BACE1 promotes chemoradiosensitivity in rectal cancer due,
in part, to ST6Gal-1 cleavage. We show that BACE1 mRNA is increased in tumors from patients who
completely respond to chemoradiotherapy. BACE1 is known to cleave ST6Gal-1, and we found through inhibitor
studies that BACE1 appear to regulate SA due to cleavage of ST6Gal-1 by BACE1. This research will evaluate
a previously unknown mechanism of resistance to chemoradiotherapy in rectal cancer, with future p...

## Key facts

- **NIH application ID:** 10339165
- **Project number:** 1R01CA265981-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Karin Marie Hardiman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $414,655
- **Award type:** 1
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10339165

## Citation

> US National Institutes of Health, RePORTER application 10339165, A novel, transferable sialylation-mediated mechanism of chemoradioresistance in GI cancer (1R01CA265981-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10339165. Licensed CC0.

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