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

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 (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Science American Association for the Advancement of Science

Book Volume: 364

Pages Range: 1156-1162

Journal Issue: 6446

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 b1,3-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.

Authors with CRIS profile

Robert Grützmann Lehrstuhl für Allgemein- und Viszeralchirurgie Christian Pilarsky Professur für Chirurgische Forschung

Involved external institutions

Cold Spring Harbor Laboratory US United States (USA) (US) Universitätsklinikum Carl Gustav Carus Dresden DE Germany (DE) University of California San Francisco (UCSF) US United States (USA) (US) University of Nebraska Medical Center (UNMC) US United States (USA) (US) Johns Hopkins University (JHU) US United States (USA) (US) Memorial Sloan Kettering Cancer Center US United States (USA) (US) University of Pennsylvania US United States (USA) (US)

How to cite

APA:

Engle, D.D., Tiriac, H., Rivera, K.D., Pommier, A., Whalen, S., Oni, T.E.,... Tuveson, D.A. (2019). The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice. Science, 364(6446), 1156-1162. https://dx.doi.org/10.1126/science.aaw3145

MLA:

Engle, Dannielle D., et al. "The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice." Science 364.6446 (2019): 1156-1162.

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