Endothelial Epac1 facilitates YAP/TAZ controlled melanoma growth and angiogenesis.

The RapGEF Epac1 has emerged as an important modulator of pro-angiogenic signalling pathways, including VEGF/VEGFR2. However, its specific role in tumor angiogenesis has remained unexplored. Here, we identify endothelial Epac1 as a critical driver of melanoma angiogenesis. Analysis of patient-derived melanomas revealed that Epac1 is markedly upregulated in tumor endothelial cells. Using both global and endothelial-specific Epac1 knockout mouse models, we demonstrate that Epac1 deletion reduced melanoma growth and vascularization following subcutaneous melanoma cell inoculation. Transcriptome profiling of tumor-associated endothelial cells from Epac1-deficient mice showed broad downregulation of pro-angiogenic and YAP/TAZ target genes. This was corroborated in vitro using an Epac1 knockout endothelial cell line, where VEGFR2 expression, YAP/TAZ nuclear translocation, and YAP/TAZ target gene transcription were all suppressed. Consistently, Epac1 deletion impaired VE-cadherin/VEGFR2 interaction, VEGF-dependent nuclear YAP/TAZ and transcriptional activity, and abolished endothelial cell alignment in response to shear stress. Collectively, our results reveal Epac1 as a central modulator of VEGFR2 and YAP/TAZ signalling, integrating angiogenic and mechanosensory cues during melanoma vascularization.