CA19 Contributes to Pancreatic Pathogenesis

Pancreatitis is a painful, sometimes recurrent condition that increases the risk of developing pancreatic cancer. The glycan carbohydrate antigen 19-9 (CA19-9) is elevated in the blood in 10%–30% of patients with pancreatitis and 75% of patients with pancreatic cancer, making it an important biomarker for both conditions, but its role is unclear. Using two mouse models with inducible CA19-9, Engle and colleagues investigated the role of the glycan in pancreatic disease. The mice exhibited pancreatitis upon CA19-9 induction, with amylase and lipase levels increasing within 24 hours of induction. Analysis of expression patterns of CA19-9 in the mouse models as well as human pancreata revealed that the expression pattern of CA19-9 is similar in the mouse models and human patients with pancreatitis and pancreatic cancer, with particularly high expression in the reactive and metaplastic ducts. Gene set enrichment analysis revealed that CA19-9 altered the expression of several genes, including some involved in extracellular matrix–receptor interactions and the ERBB, PI3K, and AKT signaling pathways. Deeper investigation of some of the enriched pathways showed that EGFR phosphorylation was increased and total EGFR was decreased—both indications of increased flux through the pathway—when CA19-9 was expressed. The increase in EGFR signaling was mediated by the matricellular protein and EGFR ligand fibulin-3 (FBLN3): CA19-9 expression led to a rise in FBLN3 glycosylation, increasing FBLN3′s association with EGFR. Further evidence that CA19-9 plays a causal role in pancreatitis development in mice is that when CA19-9 expression was ceased after three days of induction, pancreatitis resolved, and treatment with CA19-9 antibodies decreased phosphorylation of EGFR in the ductal and acinar compartments and quelled macrophage recruitment. As a consequence of CA19-9-precipitated pancreatitis and CA19-9 induction, invasive and metastatic cancer progression was markedly accelerated, shortening the time to death by more than 50% in Kras-mutant mice. Therefore, CA19-9 may be a therapeutic target worth investigating in both pancreatitis and pancreatic cancer.

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;364:1156–62.

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