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

摘要：当前列腺癌(Pca)细胞定位于骨中时，它们会遇到骨巨噬细胞。 骨髓/肿瘤微环境。巨噬细胞在肿瘤细胞凋亡清除中的特殊作用 这个过程被称为泡沫化，导致促炎免疫抑制级联反应，从而支持进一步 肿瘤生长。项目实验室在前一个周期的发现支持允许细胞凋亡的战略 细胞吞噬以强健且可分辨的方式发生，同时减少不良信号，从而 重新定位吞噬癌细胞时发生的巨噬细胞程序。关键是要找出 负责促炎性免疫抑制反应和选择性靶向的特定介质 同时促进胞吐和分解。泡细胞识别信号、T细胞免疫球蛋白和 含-3粘蛋白结构域(TIM-3)已被认为是一种强有力的识别候选蛋白 磷脂酰丝氨酸在肿瘤细胞凋亡及下游有害信号中的作用 相关的巨噬细胞。总体假设是巨噬细胞吞噬凋亡的前列腺 癌细胞触发免疫抑制信号，从而支持骨骼中的癌症生长 作为一种新的癌症治疗方法。三个目标包括：1)确定泡泡细胞吞噬的作用 巨噬细胞中的TIM-3及其促进骨肿瘤生长的能力，2)阐明靶向 前列腺癌细胞吞噬作用触发的信号转导机制 免疫抑制与骨内肿瘤生长；3)鉴定人骨肉瘤特异性基因表达特征 骨髓单核细胞/巨噬细胞在骨转移中的作用该项目的战略将 包括用选择性抗体和靶向基因精心靶向泡腾细胞受体TIM-3 泡细胞性肿瘤相关独特转录谱的小鼠模型、单细胞RNA-SEQ分析 巨噬细胞，以及TIM-3信号通路的失调与已知和合成的生化 目标。与其他PO1项目的互动将利用骨细胞衍生因子、脱落酸和 肿瘤细胞多倍体状态与巨噬细胞在肿瘤微环境中的作用 会导致灾难性的肿瘤生长。巨噬细胞在体内提供把关活动 与骨转移灶特别相关的肿瘤微环境。以信号为目标 骨髓中泡巨噬细胞的分离提供了一条新的途径，将有利于患者的设计 治疗前列腺癌骨转移。

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.