Dataset Information

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

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 ?1,3-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.

SUBMITTER: Engle DD

PROVIDER: S-EPMC6705393 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Engle Dannielle D DD Tiriac Hervé H Rivera Keith D KD Pommier Arnaud A Whalen Sean S Oni Tobiloba E TE Alagesan Brinda B Lee Eun Jung EJ Yao Melissa A MA Lucito Matthew S MS Spielman Benjamin B Da Silva Brandon B Schoepfer Christina C Wright Kevin K Creighton Brianna B Afinowicz Lauren L Yu Kenneth H KH Grützmann Robert R Aust Daniela D Gimotty Phyllis A PA Pollard Katherine S KS Hruban Ralph H RH Goggins Michael G MG Pilarsky Christian C Park Youngkyu Y Pappin Darryl J DJ Hollingsworth Michael A MA Tuveson David A DA

Science (New York, N.Y.) 20190601 6446

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<sup>a</sup>, also known as carbohydrate antigen 19-9 (CA19-9). Notably, CA19-9 expression in mice resulted in rapid and severe pancreatitis with h ...[more]

PMID: 31221853

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Project description:CA19-9 values are regularly measured in patients with pancreatic cancer. Certainly, its potential as a biomarker has been compromised by false negative results in CA19-9 negative patients and false positive results in benign pancreatico-biliary diseases. For detection of PDAC recurrence, however, CA19-9 might play an important role. The aim of this study is to analyze the accuracy of CA19-9 for detecting recurrence of pancreatic cancer. All included patients were treated either at the University Medical Center Goettingen, or at the Department of Interdisciplinary Oncology and Pneumonology, DRK-Kliniken Nordhessen, Kassel. We analyzed data of 93 patients with pancreatic cancer in the training set and 41 in the validation set, both retrospectively. Pre- and postoperative CA19-9 values and results of imaging techniques were compared. We performed ROC-analysis. The association between longitudinally measured CA19-9 values and relapse was studied with a joint model between a random effects model for the longitudinal CA19-9 measurements and a Cox proportional hazards models for the survival data. In the test set (n = 93 patients) the median follow-up time was 644 days (22 months). Overall, 71 patients (76.3%) developed recurrence during follow-up. Patients with CA19-9 values of <10kU/l were considered as CA19-9 negative patients (n = 11) and excluded from further analysis. Among the rest, approximately 60% of the patients showed significantly elevated CA19-9 prior to detection of recurrence by imaging techniques. Recurrence was shown by 2.45 times elevated CA19-9 values with 90% positive predictive value. In the validation set, 2.45 times elevated CA19-9 values showed recurrence with 90% sensitivity and 83,33% specificity, with an area under the curve of 95%. Based on measured CA19-9 values during follow-up care, the joint model estimates in recurrence-free patients the probability of recurrence-free survival. CA19-9 elevation is an early and reliable sign for PDAC recurrence. On the strength of a very high accuracy in CA19-9 positive patients, it should be considered to use CA19-9 for therapy decision even without a correlate of imaging technics. Using the joint model, follow-up care of PDAC patients after curative therapy can be stratified.

Dataset Information

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

Publications

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

Similar Datasets

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