Project Summary/Abstract Prostate cancer progression to metastatic castration-resistant disease continues to represent a major health issue. Recent advances in single-cell approaches have revealed extensive heterogeneity and complexity of cell states and cell types that drive tumor progression, and additional studies have demonstrated the central role of the tumor microenvironment. Consequently, we are proposing a new Program Project to investigate the interplay between tumor cells and their surrounding stromal and immune microenvironment in promoting prostate cancer progression, metastasis, and treatment-resistance. Our proposal is highly integrated as it brings together a multi-institutional team of four distinguished investigators (Michael Shen, Charles Sawyers, Cory Abate-Shen, Massimo Loda) in the study of prostate cancer who have complementary expertise as well as a substantial track record of collaborative interactions. We have structured our application around the following projects and cores: Project 1, led by Charles Sawyers (Memorial Sloan-Kettering Cancer Center), will investigate the immune and stromal factors that promote prostate adenocarcinoma and castration-response. Project 2, led by Cory Abate-Shen (Columbia University Irving Medical Center; CUIMC), will investigate the cell intrinsic and extrinsic drivers of prostate cancer metastasis to bone. Project 3, led by Michael Shen (CUIMC), who is also overall PI, will analyze the intrinsic and extrinsic factors that promote prostate neuroendocrine differentiation. Core A (Pathobiology), led by Massimo Loda (Weill Cornell Medicine), will provide multiple pathology-based services to all three Projects. Finally, Core B (Administrative and Data Management), led by Michael Shen, will support each Project through data management, biostatistical support, and coordination of the overall program, resource management, and review by the Internal and External Advisory Boards. Together, this highly synergistic program will elucidate the integration of intrinsic and extrinsic signals that drive castration-resistance, metastatic tropism, and neuroendocrine differentiation in prostate cancer, and will provide translational insights into the stromal and immune microenvironments for improved therapeutic approaches.