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

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

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
2
Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
3
Gladstone Institutes, San Francisco, CA 94158, USA.
4
David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Joan and Sanford I. Weill Medical College, Cornell University, New York, NY 10065, USA.
6
Department of Surgery, Universitätsklinikum Erlangen, 91054 Erlangen, Germany.
7
Institute for Pathology, Universitätsklinikum Dresden, 01307 Dresden, Germany.
8
Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA 19104, USA.
9
Department of Epidemiology and Biostatistics, Institute for Human Genetics, Quantitative Biology Institute, Institute for Computational Health Sciences, and Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, CA 94158, USA.
10
Sidney Kimmel Cancer Center, The Sol Goldman Pancreatic Cancer Research Center, and Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA.
11
Departments of Medicine and Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA.
12
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
13
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. dtuveson@cshl.edu.

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.

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PMID:
31221853
DOI:
10.1126/science.aaw3145

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