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

Science. 2019 Jun 21;364(6446):1156-1162. doi: 10.1126/science.aaw3145.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • CA-19-9 Antigen / immunology
  • CA-19-9 Antigen / metabolism*
  • Carcinogenesis / metabolism
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Chronic Disease
  • ErbB Receptors / metabolism*
  • Extracellular Matrix Proteins / metabolism
  • Fucosyltransferases / genetics
  • Fucosyltransferases / metabolism
  • Galactosyltransferases / genetics
  • Galactosyltransferases / metabolism
  • Glycosylation
  • Humans
  • Mice
  • Molecular Targeted Therapy / methods
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Pancreatitis / metabolism*
  • Pancreatitis / pathology

Substances

  • CA-19-9 Antigen
  • Efemp1 protein, mouse
  • Extracellular Matrix Proteins
  • B3GALT5 protein, human
  • Fucosyltransferases
  • Galactosyltransferases
  • 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase
  • ErbB Receptors