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

被引：216

作者：

Engle, Dannielle D. ^{[1
,2
,16
]}

Tiriac, Herve ^{[1
,2
,17
]}

Rivera, Keith D. ^{[1
]}

Pommier, Arnaud ^{[1
,2
,18
]}

Whalen, Sean ^{[3
]}

Oni, Tobiloba E. ^{[1
,2
]}

Alagesan, Brinda ^{[1
,2
]}

Lee, Eun Jung ^{[1
,2
]}

Yao, Melissa A. ^{[1
,2
]}

Lucito, Matthew S. ^{[1
,2
]}

Spielman, Benjamin ^{[1
,2
]}

Da Silva, Brandon ^{[1
,2
]}

Schoepfer, Christina ^{[1
,2
]}

Wright, Kevin ^{[1
,2
]}

Creighton, Brianna ^{[1
,2
]}

Afinowicz, Lauren ^{[1
,2
]}

Yu, Kenneth H. ^{[4
,5
]}

Gruetzmann, Robert ^{[6
]}

Aust, Daniela ^{[7
]}

Gimotty, Phyllis A. ^{[8
]}

Pollard, Katherine S. ^{[3
,9
,10
]}

Hruban, Ralph H. ^{[11
,12
]}

Goggins, Michael G. ^{[11
,12
,13
,14
]}

Pilarsky, Christian ^{[6
]}

Park, Youngkyu ^{[1
,2
]}

Pappin, Darryl J. ^{[1
]}

Hollingsworth, Michael A. ^{[15
]}

Tuveson, David A. ^{[1
,2
]}

机构：

[1] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[2] Lustgarten Fdn Pancreat Canc Res Lab, Cold Spring Harbor, NY 11724 USA

[3] Gladstone Inst, San Francisco, CA 94158 USA

[4] Mem Sloan Kettering Canc Ctr, David M Rubenstein Ctr Pancreat Canc Res, New York, NY 10065 USA

[5] Cornell Univ, Joan & Sanford I Weill Med Coll, New York, NY 10065 USA

[6] Univ Klinikum Erlangen, Dept Surg, D-91054 Erlangen, Germany

[7] Univ Klinikum Dresden, Inst Pathol, D-01307 Dresden, Germany

[8] Univ Penn, Dept Biostat Epidemiol & Informat, Philadelphia, PA 19104 USA

[9] Univ Calif San Francisco, Inst Computat Hlth Sci, Quantitat Biol Inst, Dept Epidemiol & Biostat,Inst Human Genet, San Francisco, CA 94158 USA

[10] Univ Calif San Francisco, Chan Zuckerberg Biohub, San Francisco, CA 94158 USA

[11] Johns Hopkins Univ, Sch Med, Sol Goldman Pancreat Canc Res Ctr, Sidney Kimmel Canc Ctr, Baltimore, MD 21231 USA

[12] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21231 USA

[13] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21231 USA

[14] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA

[15] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA

[16] Salk Inst Biol Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA

[17] Univ Calif San Diego, Dept Surg, La Jolla, CA 92093 USA

[18] Cochin Inst, Dept Immunol, F-75014 Paris, France

来源：

SCIENCE | 2019年 / 364卷 / 6446期

基金：

美国国家卫生研究院;

关键词：

GROWTH-FACTOR RECEPTOR; SIALYL-LEWIS-X; EGF RECEPTOR; DIFFERENTIAL-DIAGNOSIS; DUCTAL ADENOCARCINOMA; CA-19-9; ANTIGEN; TRANSGENIC MICE; CELL; EXPRESSION; CARCINOMA;

D O I：

10.1126/science.aaw3145

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 beta 1,3-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.

引用

页码：1156 / +

页数：58

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