# ST6Gal-1 contributes to pancreatic cancer initiation by promoting pancreatitis-induced acinar to ductal metaplasia

> **NIH NIH F32** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $66,390

## Abstract

Project Summary
This project will elucidate a novel mechanism by which chronic pancreatitis leads to pancreatic adenocarcinoma,
with a specific focus on one of the earliest neoplastic events, acinar to ductal metaplasia (ADM). We have
identified a new enzyme, ST6Gal1, that is involved in both pancreatitis and pancreatic adenocarcinoma. ST6Gal1 is
a membrane bound golgi sialyltransferase that adds sialic acid, in an α2-6 linkage, to N-glycosylated proteins that are
destined for the plasma membrane. ST6Gal1 has been shown to endow cells with cancer stem cell (CSC)-like
properties including greater tumor initiating potential and enhanced resistance to apoptosis through TNFR1/NFκB
signaling axis. To study the role of ST6Gal1 in pancreatic cancer, we generated a transgenic mouse line with ST6Gal1
overexpression (ST6-OE) exclusively in the pancreas and crossed these mice to a pancreatic ductal adenocarcinoma
(PDAC) mouse model (KC mice) to generate KC mice with ST6-OE in the pancreas (KC-ST6-OE mice). Compared
to KC mice (median survival = 13.6 mo) KC-ST6-OE mice demonstrate accelerated mortality (median survival = 4.3
mo). The accelerated pathogenesis observed when ST6Gal1 expression is forced suggests that ST6Gal1 may prime
the cells for transformation. These findings led us to examine if ST6Gal1 upregulation in premalignant cells can
promote neoplasia. IHC analysis of human chronic pancreatitis tissue arrays demonstrated an increase in ST6Gal1
expression in ADM lesions and co-expression of the stem/ductal transcription factor, Sox9. Therefore, we hypothesize
that during pancreatitis-induced inflammation, ST6Gal1 expression promotes acinar cell survival and thus primes the
cell for transformation. To test this hypothesis, we ask the following: i) Does ST6Gal1 promote cell survival following
inflammatory damage and promote ADM formation? ii) Given that STGal1 enhances both basal and TNF-dependent
TNFR1/NFkB signaling, does ST6Gal1 imparts stem/ductal characteristics through activating a TNFR1-NFκB-Sox9
pathway? iii) Does ST6Gal1 prime cells for KRAS driven transformation (>90% of PDAC patients display KRAS
mutation)? iv) Does ST6Gal1 promote the transition from ADM-lesions into Pancreatic intraepithelial neoplasias
(PanINs)? The findings from this study may lead to the identification of biomarkers that report whether neoplastic
transformation has occurred and lead to therapeutics that can delay or suppress this transition.

## Key facts

- **NIH application ID:** 10313181
- **Project number:** 1F32CA264906-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Michael Marciel
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $66,390
- **Award type:** 1
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313181

## Citation

> US National Institutes of Health, RePORTER application 10313181, ST6Gal-1 contributes to pancreatic cancer initiation by promoting pancreatitis-induced acinar to ductal metaplasia (1F32CA264906-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10313181. Licensed CC0.

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