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

• Published in: Science (American Association for the Advancement of Science) Vol. 364; no. 6446; pp. 1156 - 1162
• Main Authors: Engle, Dannielle D, Tiriac, Hervé, Rivera, Keith D, Pommier, Arnaud, Whalen, Sean, Oni, Tobiloba E, Alagesan, Brinda, Lee, Eun Jung, Yao, Melissa A, Lucito, Matthew S, Spielman, Benjamin, Da Silva, Brandon, Schoepfer, Christina, Wright, Kevin, Creighton, Brianna, Afinowicz, Lauren, Yu, Kenneth H, Grützmann, Robert, Aust, Daniela, Gimotty, Phyllis A, Pollard, Katherine S, Hruban, Ralph H, Goggins, Michael G, Pilarsky, Christian, Park, Youngkyu, Pappin, Darryl J, Hollingsworth, Michael A, Tuveson, David A
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 21-06-2019
• Subjects: Acute Disease; Animals; Antibodies; Antigens; Biomarkers; Blood levels; CA-19-9 Antigen - immunology; CA-19-9 Antigen - metabolism; Cancer; Carbohydrates; Carcinogenesis - metabolism; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Chronic Disease; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - metabolism; Etiology; Extracellular Matrix Proteins - metabolism; Fucosyltransferases - genetics; Fucosyltransferases - metabolism; Galactosyltransferases - genetics; Galactosyltransferases - metabolism; Glycan; Glycosylation; Growth factors; Humans; Medical treatment; Mice; Molecular Targeted Therapy - methods; Organoids; Pancreatic cancer; Pancreatic diseases; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pancreatitis; Pancreatitis - metabolism; Pancreatitis - pathology; Pathogenesis; Proteins; Therapeutic applications; Transgenic animals; Transgenic mice
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aaw3145

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-Lewis
, 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
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.