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Molecular cancer therapeutics

The NOTCH ligand JAGGED2 promotes pancreatic cancer metastasis independent of NOTCH signaling activation.


PMID 25351917

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal disease with a high rate of metastasis. Numerous signaling events have been implicated in the molecular pathogenesis of this neoplasm. Aberrantly high expression of JAGGED2, one of the NOTCH ligands, often occurs in human PDAC. However, what role JAGGED2 plays in the disease development and whether JAGGED2 executes its function through activating NOTCH signaling remain to be determined. We report here that JAGGED2 plays a critical role in promoting PDAC metastasis in vitro and in vivo. Depletion of JAGGED2, but not its homolog JAGGED1, profoundly inhibited both migration and invasion without influencing cell proliferation. Furthermore, reconstitution of JAGGED2 expression rescued the migratory defect. Surprisingly, neither pharmacologic nor genetic inhibition of NOTCH downstream signaling resulted in obvious defect in metastasis. Instead, depletion of NOTCH1 expression per se gave rise to migratory defects similar to JAGGED2 ablation. Moreover, blockade of ligand-receptor interaction by a specific JAGGED2-Fc fusion protein dramatically inhibited PDAC cell migration, suggesting that tumor metastasis relies on physical interactions of JAGGED2-NOTCH1 but not Notch downstream signaling activation. Taken together, our data reveal a novel role of NOTCH in regulation of PDAC metastasis, and identify JAGGED2 as a critical mediator in this event. These findings also provide rationale for developing small molecules or biologic agents targeting JAGGED2 for therapeutic intervention.