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

Clausen, Thomas Mandel, Weiss, Ryan J, Tremblay, Jacob R, Kellman, Benjamin P, Coker, Joanna, Dworkin, Leo A, Rodriguez, Jessica P, Chang, Ivy M, Chen, Timothy, Padala, Vikram, Karlsson, Richard, Song, Hyemin, Peck, Kristina L, Ogawa, Satoshi, Sandoval, Daniel R, Joshi, Hiren J, Wang, Gaowei, Ferguson, L Paige, Bhalerao, Nikita, Moores, Allison, Reya, Tannishtha, Sander, Maike, Caffrey, Thomas C, Grem, Jean L, Aicher, Alexandra, Heeschen, Christopher, Le, Dzung, Lewis, Nathan E, Hollingsworth, Michael A, Grandgenett, Paul M, Bellis, Susan L, Miller, Rebecca L, Fuster, Mark M, Dawson, David W, Engle, Dannielle D, Esko, Jeffrey D (November 2025) Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis. Journal of Clinical Investigation, 135 (22). ISSN 1558-8238

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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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types
CSHL Authors:	Ferguson, Lesley
Communities:	CSHL labs > Tuveson lab CSHL Post Doctoral Fellows
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	17 November 2025
Date Deposited:	24 Nov 2025 13:37
Last Modified:	24 Nov 2025 13:37
PMCID:	PMC12618072
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42010

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