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The exchange protein activated by cAMP (EPAC) is a cell signaling protein that regulates pathways important for cell growth, survival, and migration, which are commonly associated with cancer progression, but are also very important for regulation of viral infectivity. EPAC antagonism has been explored as a broad-spectrum antiviral strategy, while selective EPAC activation with cAMP analogs has been found to increase virus replication and enhance therapeutic outcome of oncolytic virotherapy. However, systemic EPAC agonism bears risk of cardiovascular complications and may potentiate cancer progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A constitutively active construct of EPAC was encoded into an oncolytic vaccinia virus (VV) and screened using plaque assays, spheroid infections, and Transwell migration assays for its ability to enhance virus replication and spread. In vivo luminescence imaging, titering and immunohistochemical staining was used to measure virus dissemination in primary injected tumors and to track their spread to distal untreated tumors. The impact of the VV-EPAC virus on the immune landscape of MC38 tumors was investigated by flow cytometry, ELISPOTs and cytokine ELISAs, while its overall therapeutic efficacy was explored in MC38, CT26LacZ, and B16F10 models. Combinational synergy was also tested with capecitabine and oxaliplatin chemotherapy, as well as with partial surgical resection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The EPAC-expressing virus exhibited an increase in migrative ability both in cell culture and in vivo, due in part to remodeling of the actin cytoskeleton leading to intercellular nanotube-like structures and enhanced syncytia formation. It reduced tumor burden and increased survival in multiple colorectal cancer models and reshaped the tumor microenvironment by inducing angiogenesis and recruiting CD8+T cells. The EPAC-expressing virus also synergized with conventional chemotherapy and exhibited a remarkable therapeutic benefit when used together with surgical resection to treat a metastatic melanoma model. Despite the noted benefits that EPAC offers to virus and cancer growth, no significant increase in off-target replication, cytotoxicity, or disease progression was observed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Altogether, the encoding of cellular signaling proteins into oncolytic viruses that modulate the intracellular and extracellular environments of tumors to create conditions favorable for virus replication and dissemination appears as a promising strategy to treat tumors and synergize with other conventional cancer therapies.<\/jats:p>\n                  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