| Literature DB >> 31221853 |
Dannielle D Engle1,2, Hervé Tiriac1,2, Keith D Rivera1, Arnaud Pommier1,2, Sean Whalen3, Tobiloba E Oni1,2, Brinda Alagesan1,2, Eun Jung Lee1,2, Melissa A Yao1,2, Matthew S Lucito1,2, Benjamin Spielman1,2, Brandon Da Silva1,2, Christina Schoepfer1,2, Kevin Wright1,2, Brianna Creighton1,2, Lauren Afinowicz1,2, Kenneth H Yu4,5, Robert Grützmann6, Daniela Aust7, Phyllis A Gimotty8, Katherine S Pollard3,9, Ralph H Hruban10, Michael G Goggins10,11, Christian Pilarsky6, Youngkyu Park1,2, Darryl J Pappin1, Michael A Hollingsworth12, David A Tuveson13,2.
Abstract
Glycosylation alterations are indicative of tissue inflammation and neoplasia, but whether these alterations contribute to disease pathogenesis is largely unknown. To study the role of glycan changes in pancreatic disease, we inducibly expressed human fucosyltransferase 3 and β1,3-galactosyltransferase 5 in mice, reconstituting the glycan sialyl-Lewisa, also known as carbohydrate antigen 19-9 (CA19-9). Notably, CA19-9 expression in mice resulted in rapid and severe pancreatitis with hyperactivation of epidermal growth factor receptor (EGFR) signaling. Mechanistically, CA19-9 modification of the matricellular protein fibulin-3 increased its interaction with EGFR, and blockade of fibulin-3, EGFR ligands, or CA19-9 prevented EGFR hyperactivation in organoids. CA19-9-mediated pancreatitis was reversible and could be suppressed with CA19-9 antibodies. CA19-9 also cooperated with the KrasG12D oncogene to produce aggressive pancreatic cancer. These findings implicate CA19-9 in the etiology of pancreatitis and pancreatic cancer and nominate CA19-9 as a therapeutic target.Entities:
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Year: 2019 PMID： 31221853 PMCID： PMC6705393 DOI： 10.1126/science.aaw3145
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 63.714