The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice.
Fiche publication
Date publication
juin 2019
Journal
Science (New York, N.Y.)
Auteurs
Membres identifiés du Cancéropôle Est :
Dr POMMIER Arnaud
Tous les auteurs :
Engle DD, Tiriac H, Rivera KD, Pommier A, Whalen S, Oni TE, Alagesan B, Lee EJ, Yao MA, Lucito MS, Spielman B, Da Silva B, Schoepfer C, Wright K, Creighton B, Afinowicz L, Yu KH, Grützmann R, Aust D, Gimotty PA, Pollard KS, Hruban RH, Goggins MG, Pilarsky C, Park Y, Pappin DJ, Hollingsworth MA, Tuveson DA
Lien Pubmed
Résumé
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.
Mots clés
Acute Disease, Animals, CA-19-9 Antigen, immunology, Carcinogenesis, metabolism, Carcinoma, Pancreatic Ductal, metabolism, Cell Line, Tumor, Chronic Disease, ErbB Receptors, metabolism, Extracellular Matrix Proteins, metabolism, Fucosyltransferases, genetics, Galactosyltransferases, genetics, Glycosylation, Humans, Mice, Molecular Targeted Therapy, methods, Pancreatic Neoplasms, metabolism, Pancreatitis, metabolism
Référence
Science. 2019 06 21;364(6446):1156-1162