The recent discovery of a new family of cAMP sensor proteins, exchange protein activated by cAMP (EPAC), ushered in a new era in cAMP signaling. EPAC is composed of two main isoforms, EPAC1 and EPAC2, whose roles in mediating cAMP effects in various cellular contexts remains relatively unclear, and must be elucidated to examine the therapeutic potential of these proteins. This work investigated the role of EPAC1 in promoting invasion and metastasis of pancreatic ductal adenocarcinoma (PDA) and immune regulation, through modulation of the activity of regulatory T-cells (Treg), a subset of T-cells that suppress the immune system and maintain immune tolerance.

In three common PDA cell lines, AsPC-1, PANC-1, and MIA PaCa-2, suppression/inhibition of EPAC1 reduced invasion/migration in transwell invasion/migration and wound healing assays. In an in vivo orthotopic metastatic PDA mouse model, suppression/inhibition of EPAC1 significantly reduced local invasion and distant metastasis of MIA PaCa-2 as determined by in vivo bioluminescence imaging and histological evaluation of the number of metastatic foci in the liver. Mechanistically, FACS-based and protein fractionation assays showed that EPAC1 facilitates activation and trafficking of integrin β1, both of which play a critical role in mediating cancer cell motility.

Inhibition/knockout of EPAC1 in either Treg or effector T-cells (Teff) decreased Treg-mediated suppression of Teff, while the impact of EPAC1 inhibition/knockout was additive, as determined by an in vitro suppression assay. Mechanistically, inhibition/knockout of EPAC1 up-regulated STAT3 activation and desensitized T-cells to TGF-β1 signaling. These results suggest that EPAC1 enhances the potency of Treg cells and simultaneously sensitizes Teff cells to suppression.

PDA has a dismal prognosis with ~ 95% mortality rate, in large part because of its high metastatic potential and dense desmoplastic microenvironment, which efficiently recruits and induces Treg cells to quell the body’s antitumor immune response. The findings presented in this work suggest that EPAC1 inhibitors might have excellent therapeutic potential as anti-PDA agents that can concurrently reduce PDA metastasis and enhance antitumor immunity.

cAMP, EPAC1, Metastasis, Regulatory T-Cells