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

Dannielle D. Engle, Hervé Tiriac, Keith D. Rivera, Arnaud Pommier, Sean Whalen, Tobiloba E. Oni, Brinda Alagesan, Eun Jung Lee, Melissa A. Yao, Matthew S. Lucito, Benjamin Spielman, Brandon Da Silva, Christina Schoepfer, Kevin Wright, Brianna Creighton, Lauren Afinowicz, Kenneth H. Yu, Robert Grützmann, Daniela Aust, Phyllis A. GimottyKatherine S. Pollard, Ralph H. Hruban, Michael G. Goggins, Christian Pilarsky, Youngkyu Park, Darryl J. Pappin, Michael A. Hollingsworth, David A. Tuveson

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1156-1162
Number of pages7
JournalScience
Volume364
Issue number6446
DOIs
StatePublished - Jan 1 2019

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Pancreatic Neoplasms
Pancreatitis
Polysaccharides
Carbohydrates
Antigens
Epidermal Growth Factor Receptor
galactoside 3-fucosyltransferase
Organoids
Galactosyltransferases
Pancreatic Diseases
Glycosylation
Oncogenes
Ligands
Inflammation
Antibodies
Neoplasms
Proteins

ASJC Scopus subject areas

  • General

Cite this

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://doi.org/10.1126/science.aaw3145

The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice. / Engle, Dannielle D.; Tiriac, Hervé; Rivera, Keith D.; Pommier, Arnaud; Whalen, Sean; Oni, Tobiloba E.; Alagesan, Brinda; Lee, Eun Jung; Yao, Melissa A.; Lucito, Matthew S.; Spielman, Benjamin; Silva, Brandon Da; Schoepfer, Christina; Wright, Kevin; Creighton, Brianna; Afinowicz, Lauren; Yu, Kenneth H.; Grützmann, Robert; Aust, Daniela; Gimotty, Phyllis A.; Pollard, Katherine S.; Hruban, Ralph H.; Goggins, Michael G.; Pilarsky, Christian; Park, Youngkyu; Pappin, Darryl J.; Hollingsworth, Michael A.; Tuveson, David A.

In: Science, Vol. 364, No. 6446, 01.01.2019, p. 1156-1162.

Research output: Contribution to journalArticle

Engle, DD, Tiriac, H, Rivera, KD, Pommier, A, Whalen, S, Oni, TE, Alagesan, B, Lee, EJ, Yao, MA, Lucito, MS, Spielman, B, Silva, BD, 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, 'The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice', Science, vol. 364, no. 6446, pp. 1156-1162. https://doi.org/10.1126/science.aaw3145
Engle DD, Tiriac H, Rivera KD, Pommier A, Whalen S, Oni TE et al. The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice. Science. 2019 Jan 1;364(6446):1156-1162. https://doi.org/10.1126/science.aaw3145
Engle, Dannielle D. ; Tiriac, Hervé ; Rivera, Keith D. ; Pommier, Arnaud ; Whalen, Sean ; Oni, Tobiloba E. ; Alagesan, Brinda ; Lee, Eun Jung ; Yao, Melissa A. ; Lucito, Matthew S. ; Spielman, Benjamin ; Silva, Brandon Da ; Schoepfer, Christina ; Wright, Kevin ; Creighton, Brianna ; Afinowicz, Lauren ; Yu, Kenneth H. ; Grützmann, Robert ; Aust, Daniela ; Gimotty, Phyllis A. ; Pollard, Katherine S. ; Hruban, Ralph H. ; Goggins, Michael G. ; Pilarsky, Christian ; Park, Youngkyu ; Pappin, Darryl J. ; Hollingsworth, Michael A. ; Tuveson, David A. / The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice. In: Science. 2019 ; Vol. 364, No. 6446. pp. 1156-1162.
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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.",
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AU - Engle, Dannielle D.

AU - Tiriac, Hervé

AU - Rivera, Keith D.

AU - Pommier, Arnaud

AU - Whalen, Sean

AU - Oni, Tobiloba E.

AU - Alagesan, Brinda

AU - Lee, Eun Jung

AU - Yao, Melissa A.

AU - Lucito, Matthew S.

AU - Spielman, Benjamin

AU - Silva, Brandon Da

AU - Schoepfer, Christina

AU - Wright, Kevin

AU - Creighton, Brianna

AU - Afinowicz, Lauren

AU - Yu, Kenneth H.

AU - Grützmann, Robert

AU - Aust, Daniela

AU - Gimotty, Phyllis A.

AU - Pollard, Katherine S.

AU - Hruban, Ralph H.

AU - Goggins, Michael G.

AU - Pilarsky, Christian

AU - Park, Youngkyu

AU - Pappin, Darryl J.

AU - Hollingsworth, Michael A.

AU - Tuveson, David A.

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N2 - 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.

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