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

3-O-sulfation of heparan sulfate is the key determinant for the binding and activation of the serine protease inhibitor antithrombin. This interaction is the basis of the anti-thrombotic treatment using heparin, a fractionated form of heparan sulfate derived from porcine entrails and bovine lung. Antithrombin-binding heparan sulfate (HSAT) is also expressed in human tissues, although it is generally thought to be rare and restricted to endothelial cells, mast cells, or follicular fluid. Here we show that HSAT is ubiquitously expressed in the basement membranes of epithelial cells in multiple tissues, indicating that HSAT is more abundant than previously realized. HSAT is expressed by healthy pancreatic ductal cells and its expression is increased in neoplastic progression of premalignant pancreatic intraepithelial neoplasia lesions (PanINs) but reduced in mature metastatic pancreatic ductal adenocarcinoma (PDAC). Genetic inactivation of HS3ST1, a key enzyme in HSAT synthesis, in murine PDAC cells eliminated HSAT expression, induced an inflammatory phenotype, suppressed markers of apoptosis, and increased metastasis in an experimental mouse model. HSAT-positive PDAC tumors bind AT, which inhibits the generation of active thrombin by tissue factor (TF) and Factor VIIa. These findings suggest that expression of HSAT acts as a tumor suppressor through recruitment of AT and that the loss of HSAT in progression to PDAC increases inflammation and metastatic potential. Furthermore, plasma from PDAC patients showed an accumulation of HSAT suggesting its possible utility as a marker of tumor formation. Fully understanding the function of HSAT in healthy tissues and how it contributes to pancreatic tumorigenesis could pave the way for the development of novel strategies for early diagnosis and potential therapy.