ABSTRACT Cutaneous melanoma arises from melanocytes in the skin. Exposure to solar ultraviolet (UV) radiation is a significant risk factor. Deployment of US military personnel around the world in areas of high UV index thus increases risk of melanoma during and after military service. If diagnosed early, excision of the primary tumor in the skin can be curative. However, the five-year survival rates decrease precipitously as melanoma metastasizes to local and regional lymph nodes and distant organs. Despite the recent successes and promise of targeted therapies and immunotherapy, early diagnosis and treatment of the localized primary cancer remain the best strategies to reduce cancer mortality. Therefore, a detailed understanding of the molecular mechanisms involved in melanoma tumor progression is critical for accurate and reliable diagnosis and treatment of aggressive cutaneous melanoma. Cyclic AMP (cAMP) signaling pathway plays a critical role in melanocyte proliferation and differentiation. This pathway is initiated upon elevation of intracellular cAMP by the catalytic activity of adenylyl cyclases and transduced through protein kinase A and transcription factor CREB culminating in expression of cAMP-responsive genes including the melanocyte master regulator, MITF. The role for cAMP signaling pathway in melanoma is not fully understood. Employing a human primary melanoma tissue microarray (TMA), a panel primary and metastatic melanoma cell lines and the BrafV600E/Pten-/- mouse model for melanoma, we recently demonstrated that cAMP signaling plays opposite roles in primary and metastatic melanoma cells, i. e., as a pro- proliferative signal in primary and as anti-proliferative signal in metastatic cells. We also showed that this switch in the cAMP of action is mediated by the alternative cAMP signaling axis involving EPAC-RAP1 (Exchange factor directly activated by cAMP- Ras-related protein 1). Additional studies showed that EPAC promotes cell cycle progression, activates mTORC1 signaling, and regulates cellular metabolism and mitochondrial ROS production selectively in primary melanoma cells. Furthermore, studies using a panel of primary and metastatic melanoma cell lines derived from the same patient revealed that the switch in the functions of EPAC occurs progressively during melanoma metastasis suggesting that EPAC is a critical component for the growth of primary melanoma and that rewiring of signaling networks during tumor progression abolish EPAC dependency in metastatic melanoma. Here, we propose to test the hypotheses that a) oncogenic transformation of melanocytes activates EPAC signaling and EPAC acts as a critical signaling node to suppress stress induced ROS generation, promote senescence escape and primary melanoma development, and b) gene expression changes and metabolic adaptions that occur during metastasis progressively abolish EPAC dependency. The specific aims of this application are: 1) Establish the role of EPAC in melano...