Abstract PR12: The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice

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 b1,3-galactosyltransferase 5 in mice, reconstituting the glycan sialyl-Lewis a, 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, 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. This abstract is also being presented as Poster C16. Citation Format: Dannielle Engle, Herve Tiriac, Keith Rivera, Arnaud Pommier, Sean Whalen, Tobiloba Oni, Brinda Alagesan, Eun Lee, Melissa Yao, Matthew Lucito, Benjamin Spielman, Kenneth Yu, Robert Grutzmann, Daniela Aust, Phyllis Gimotty, Katherine Pollard, Ralph Hruban, Michael Goggins, Christian Pilarsky, Young Park, Darryl Pappin, Michael A. Hollingsworth, David Tuveson. The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR12.