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

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

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.

Authors

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

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Figure 3

HSAT is expressed by ductal cells in the healthy pancreas.

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HSAT is expressed by ductal cells in the healthy pancreas. (A) The graph...
(A) The graphic illustrates the staining procedure and the effect of HSase treatment. AT staining of FFPE section of human pancreatic tissue, with and without heparin lyase (HSase) treatment. AT staining was intense along the basolateral side of the normal ductal cells (yellow arrowheads) and blood vessels (orange arrowheads). The image on the right displays the acinar compartment. AT staining is seen in the blood vessels as expected (orange arrowheads) and occasional cells in the stroma (white arrowheads). Bound AT, red; DAPI-stained nuclei blue; autofluorescence, green. (B–D) Analysis of HS3ST1 mRNA expression in a single-cell sequence data set from healthy pancreas. (B and C) Uniform Manifold Approximation and Projection (UMAP) visualization of single-cell RNA-Seq clusters based on markers identifying acinar, beta, alpha, delta, and ductal cell compartments. Each point represents a single cell, and cells are positioned based on similarity in gene expression. (D) HS3ST1 mRNA expression in the identified clusters. The level of expression of HS3ST1 and known cell markers (CFTR [ductal], REG1A [acinar], GCG [alpha cells], INS [beta cells], and SST [delta cells]) are shown. HS3ST1 expression is highest in the ductal cell fraction.