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

Engle, D. D., Tiriac, H., Rivera, K. D., Pommier, A., Whalen, S., Oni, T. E., Alagesan, B., Lee, E. J., Yao, M. A., Lucito, M. S., Spielman, B., Da Silva, B., Schoepfer, C., Wright, K., Creighton, B., Afinowicz, L., Yu, K. H., Grutzmann, R., Aust, D., Gimotty, P. A., Pollard, K. S., Hruban, R. H., Goggins, M. G., Pilarsky, C., Park, Y., Pappin, D. J., Hollingsworth, M. A., Tuveson, D. A. (June 2019) The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice. Science, 364 (6446). pp. 1156-1162. ISSN 0036-8075

URL: https://www.ncbi.nlm.nih.gov/pubmed/31221853

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 beta1,3-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 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 Kras(G12D) 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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders Investigative techniques and equipment diseases & disorders > neoplasms organism description > animal Investigative techniques and equipment > cell culture > cancer organoids Investigative techniques and equipment > cell culture organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > pancreatic cancer organism description > animal > mammal > rodent diseases & disorders > cancer > cancer types
CSHL Authors:	Tuveson, David A. Pappin, Darryl J. Engle, Dannielle Tiriac, Herve Rivera, Keith Pommier, Arnaud Oni, Tobiloba Alagesan, Brinda Lee, Eunjung Yao, Melissa Lucito, Matthew S Spielman, Benjamin Da Silva, Brandon Schoepfer, Christina Wright, Kevin Creighton, Brianna Afinowicz, Lauren Park, Youngkyu
Communities:	CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Shared Resources > Antibody and Phage Display Service CSHL labs > Pappin lab CSHL labs > Tuveson lab CSHL Cancer Center Shared Resources > Animal Shared Resource
Depositing User:	Matthew Dunn
Date:	21 June 2019
Date Deposited:	29 Jul 2019 13:52
Last Modified:	02 Feb 2024 14:58
PMCID:	PMC6705393
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/38156

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