# Truncated O-glycan-dependent mechanisms inducing metastatic dissemination in pancreatic cancer

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $488,488

## Abstract

Pancreatic cancer (PC) is the fourth leading cause of cancer death and often goes undiagnosed until it has already
advanced and metastasized. Aberrant changes in O-glycans, such as increased expression of truncated
carbohydrate antigens (Tn, sialylated Tn/STn), are commonly observed in PC. However, the mechanistic
involvement of these truncated O-glycan structures in PC progression and metastasis is under-explored. Hence,
our study is focused on investigating the mechanistic role of truncated O-glycans during early metastatic
dissemination in PC. The O-glycosyltransferase Core 1 β1,3-Galactosyltransferase (C1GALT1) catalyzes the
second step of mucin-type O-glycan biosynthesis by adding galactose to the first sugar N-acetylgalactosamine
(Tn) that forms the Core 1 carbohydrate structure. Such structures are usually elongated to mature O-glycans
found on normal tissue, but their extension may be truncated at the Tn-glycan stage during cancer due to inactive
C1GALT1 activity. Our preliminary data demonstrated the loss of O-glycosyltransferase activity, C1GALT1, in a
subset of (poorly differentiated) human PC tissue. Further, CRISPR/Cas9-based C1GALT1 knockout (KO) in PC
cells resulted in aberrant O-glycosylation (increased Tn and STn glycans). Along with glycan alterations presented
upon oncogenic glycoproteins (mucin glycoproteins and cancer stem cell markers), our studies also indicate
increased tumorigenicity and metastasis of C1GALT1 KO PC cells. We have also observed O-glycan truncation
present on CD44, a cancer stem cell marker, in C1GALT1 models. Interestingly, knockout of C1galt1 along with
KrasG12D and Trp53R172H/+ mutations in mouse models resulted in early-onset (in 3 weeks) and early distant
metastasis (in 10 weeks) of PC. Based on these observations, our major goal is to investigate the mechanistic
role of truncated O-glycans in PC progression and metastasis. Based on these observations, we hypothesize
that "Truncated O-glycans on cancer-associated glycoproteins (mucins and stemness markers) induce the early
onset of progression and metastatic dissemination in pancreatic cancer." To test this hypothesis, the following
aims are proposed. The first aim will investigate the functional impact of C1GALT1 expression and aberrant
glycosylation profile on cancer-associated glycoproteins in pancreatic cancer. The second aim will elucidate how
truncated O-glycans (such as Tn and STn) on membrane-bound mucins and stemness markers facilitate
pancreatic cancer metastasis. The third aim will determine, in vivo, the impact of truncated O-glycans in the early
onset of pancreatic cancer metastasis using C1galt1 knockout KC and KPC mice. The proposed studies will
establish the association of aberrant expression of truncated Tn and STn glycans with differential membrane-
bound mucin function during PC progression and metastasis. This study will significantly contribute to our
knowledge of mucin glycobiology in cancer. Altogether, this proposed study will a...

## Key facts

- **NIH application ID:** 10889122
- **Project number:** 5R01CA273349-03
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Surinder K. Batra
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $488,488
- **Award type:** 5
- **Project period:** 2022-08-12 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889122

## Citation

> US National Institutes of Health, RePORTER application 10889122, Truncated O-glycan-dependent mechanisms inducing metastatic dissemination in pancreatic cancer (5R01CA273349-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10889122. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*