Despite the introduction of new therapies for advanced-stage prostate cancer, the development of castrate-resistant and metastatic disease is incurable, and carries high morbidity and mortality. This is arguably the most urgent, and largely unmet, medical need in the management of prostate cancer patients. However, our understanding of metastatic competency in these settings is sketchy, as we lack a clear picture of how tumors acquire invasive potential, what their metabolic needs are or whether the host immune response has a role in this process. The present continuation of CA140043 for a new grant cycle is designed to bridge this knowledge gap. Our overarching goals are to reach a better mechanistic understanding of prostate cancer metastasis, and identify new, “actionable” therapeutic targets for advanced disease settings. Three highly integrated and collaborative Projects will tackle these questions. The proposed studies will elucidate a novel interface between mitochondrial metabolic reprogramming and the mechanics of prostate cancer invasion (Project 1), characterize how prostate cancer-released exosomes mediate intercellular communication and increased tumor cell motility (Project 2), and define the role of local immunosuppressive checkpoints mediated by Myeloid-Derived Suppressor Cells in prostate cancer progression (Project 3). Two Cores fully integrated in the scientific objectives of the Projects will help fulfill the specific aims. In particular, an Administration and Biostatistics Core (Core A) will serve as a research enhancement vehicle for the Program as a whole. Core A will promote the highest level of scientific integration between Research Projects and Cores (i), provide state-of-the-art study design, biostatistical support and quantitative data analysis for all three Projects (ii), coordinate collaborative interactions with advisory bodies, including an External Advisory Board (EAB) and an Internal Steering Committee (iii), ensure unfettered access to clinically-annotated patient material in support of Project 3 (iv), and manage all operational, financial and outreach initiatives of the Program (v). Building on the success and experience of the last grant cycle, Core A relies on a team of seasoned investigators and administrators with a long history of collaboration and proven operational expertise. The Core has been configured to provide a straightforward and cost-effective management of the Program, avoid duplications, promote scientific collaboration to the fullest, and help broadly disseminate the research findings of each Project.