Project 4: The role of bone marrow macrophages in skeletal metastasis

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Abstract: When prostate cancer (PCa) cells localize in bone they encounter osteal macrophages in the marrow/tumor microenvironment. The specific function of macrophages in apoptotic cancer cell clearance, a process termed efferocytosis, leads to a pro-inflammatory immunosuppressive cascade that supports further tumor growth. Findings from the project laboratory in the previous cycle support a strategy to allow apoptotic cell engulfment to occur in a robust and resolving manner while reducing the adverse signaling and hence reorienting the macrophage program that occurs when they engulf a cancer cell. It is critical to identify the specific mediators responsible for the pro-inflammatory immunosuppressive response and selectively target them while promoting efferocytosis and resolution. An efferocytic recognition signal, T cell immunoglobulin and mucin-domain containing-3 (Tim-3) has been identified as a strong candidate in the recognition of phosphatidylserine on an apoptotic cell and the downstream deleterious signaling operative in tumor associated macrophages. The overall hypothesis is that macrophage efferocytosis of apoptotic prostate cancer cells triggers immunosuppressive signaling which supports cancer growth in bone that can be targeted as a novel cancer therapy. Three aims include; 1) To determine the role of efferocytosis-induced Tim-3 in macrophages and its ability to accelerate tumor growth in bone, 2) To elucidate targetable mechanisms of the signaling pathways triggered by efferocytosis of prostate cancer cells that support immunosuppression and tumor growth in bone, and 3) To identify the specific gene-expression signature of bone marrow efferocytic monocytes/macrophages during skeletal metastasis. Strategies for this project will include meticulous targeting of the efferocytic receptor Tim-3 with selective antibodies and a gene targeted mouse model, single cell RNA-seq analyses of the unique transcriptional profile of efferocytic tumor associated macrophages, and dysregulation of the signaling pathway for Tim-3 with known and synthesized biochemical targets. Interactions with the other PO1 projects will leverage osteocytic derived factors, abscisic acid, and the polyploid status of cancer cells to identify their roles in the tumor microenvironment that macrophages orchestrate to lead to catastrophic tumor growth. Efferocytic macrophages provide gatekeeping activities in the tumor microenvironment that are particularly relevant in the skeletal metastatic lesion. Targeting the signaling of efferocytic macrophages in the bone marrow provides a new avenue that will benefit the design of patient therapeutics for the treatment of prostate cancer skeletal metastasis.