Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis

3-O-sulfation of heparan sulfate (HS) is the key determinant for binding and activation of antithrombin III (AT). This interaction is the basis of heparin treatment to prevent thrombotic events and excess coagulation. Antithrombin-binding HS (HSAT) is expressed in human tissues but is thought to be expressed in the subendothelial space, mast cells, and follicular fluid. Here, we show that HSAT is ubiquitously expressed in the basement membranes of epithelial cells in multiple tissues. In the pancreas, HSAT is expressed by healthy ductal cells, and its expression is increased in premalignant pancreatic intraepithelial neoplasia lesions but not in pancreatic ductal adenocarcinoma (PDAC). Inactivation of HS3ST1, a key enzyme in HSAT synthesis, in PDAC cells eliminated HSAT expression, induced an inflammatory phenotype, suppressed markers of apoptosis, and increased metastasis in an experimental mouse PDAC model. HSAT-positive PDAC cells bind AT, which inhibits the generation of active thrombin by tissue factor and factor VIIa. Furthermore, plasma from patients with PDAC showed accumulation of HSAT, suggesting its potential as a marker of tumor formation. These findings suggest that HSAT exerts a tumor-suppressing function through recruitment of AT and that the decrease in HSAT during progression of pancreatic tumorigenesis increases inflammation and metastatic potential.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-09-09
DOI
https://doi.org/10.1172/jci184172
Citations
1
Primary Topic
Proteoglycans and glycosaminoglycans research
Type
article
Field-Weighted Citation Impact
1.15
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article

Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis

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1 citations
Journal of Clinical Investigation
Proteoglycans and glycosaminoglycans research
1.15
article

Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis

Jessica Wang Rodriguez, Alexandra Aicher, Hiren J. Joshi, Mark M. Fuster, Kristina Peck, Thomas C. Caffrey, Ivy R. Chang, Michael Anthony Hollingsworth, Jacob R. Tremblay, Ryan J. Weiss, Nikita Bhalerao, Tseng-hui Timothy Chen, Susan L. Bellis, Leo Alexander Dworkin, David W. Dawson, Gaowei Wang, Jean L. Grem, Daniel R. Sandoval, Benjamin P. Kellman, Tannishtha Reya, Vikram Padala, Christopher Heeschen, Joanna Coker, Maike Sander, Richard Karlsson, Jeffrey D. Esko, Dannielle D. Engle, Nathan E. Lewis, L. Paige Ferguson, Rebecca L. Miller, Paul M. Grandgenett, Satoshi Ogawa, Thomas Mandel Clausen, Hyemin Song, Dzung Le, Allison Moores
article en
1 citations

Abstract

3-O-sulfation of heparan sulfate (HS) is the key determinant for binding and activation of antithrombin III (AT). This interaction is the basis of heparin treatment to prevent thrombotic events and excess coagulation. Antithrombin-binding HS (HSAT) is expressed in human tissues but is thought to be expressed in the subendothelial space, mast cells, and follicular fluid. Here, we show that HSAT is ubiquitously expressed in the basement membranes of epithelial cells in multiple tissues. In the pancreas, HSAT is expressed by healthy ductal cells, and its expression is increased in premalignant pancreatic intraepithelial neoplasia lesions but not in pancreatic ductal adenocarcinoma (PDAC). Inactivation of HS3ST1, a key enzyme in HSAT synthesis, in PDAC cells eliminated HSAT expression, induced an inflammatory phenotype, suppressed markers of apoptosis, and increased metastasis in an experimental mouse PDAC model. HSAT-positive PDAC cells bind AT, which inhibits the generation of active thrombin by tissue factor and factor VIIa. Furthermore, plasma from patients with PDAC showed accumulation of HSAT, suggesting its potential as a marker of tumor formation. These findings suggest that HSAT exerts a tumor-suppressing function through recruitment of AT and that the decrease in HSAT during progression of pancreatic tumorigenesis increases inflammation and metastatic potential.

Journal of Clinical InvestigationVol. 135(22)
Bishop's University (CA), University of Hawaiʻi at Mānoa (US), University of Copenhagen (DK), Salk Institute for Biological Studies (US), University of California, Los Angeles (US), University of Georgia (US), University of Massachusetts Chan Medical School (US), China Medical University (TW), Cold Spring Harbor Laboratory (US), Brown University (US), Columbia University Irving Medical Center (US), UC San Diego Health System (US), Ragon Institute of MGH, MIT and Harvard (US), University of Alabama at Birmingham (US), University of California San Diego (US), Sanford Consortium for Regenerative Medicine (US), VA San Diego Healthcare System (US), University of California San Diego Medical Center (US), La Jolla Bioengineering Institute (US), Cellular Research (United States) (US), Candiolo Cancer Institute (IT), University of Nebraska Medical Center (US)
Openalex Percentile: Top 20%
Proteoglycans and glycosaminoglycans research
1.15
DOIOpen Access PDFOpenAlex
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