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

翻译后摘要：当前列腺癌（PCa）细胞定位于骨，他们遇到骨巨噬细胞在 骨髓/肿瘤微环境。巨噬细胞在凋亡癌细胞清除中的特异性功能 一种称为红细胞增多症的过程，导致促炎性免疫抑制级联反应， 肿瘤生长项目实验室在前一周期的发现支持了一种策略， 细胞吞噬以稳健和解决的方式发生，同时减少不良信号传导， 重新定位吞噬癌细胞时发生的巨噬细胞程序。关键是要确定 负责促炎性免疫抑制反应的特异性介质，并选择性靶向 同时促进红细胞增多和消退。免疫细胞识别信号、T细胞免疫球蛋白和 含粘蛋白结构域3（Tim-3）已被确定为识别 磷脂酰丝氨酸对凋亡细胞和下游有害信号在肿瘤中起作用 相关巨噬细胞。总的假设是凋亡前列腺的巨噬细胞吞噬功能 癌细胞触发免疫抑制信号，支持骨中的癌症生长， 作为一种新的癌症治疗方法。三个目的包括：1）确定巨噬细胞诱导的 巨噬细胞中的Tim-3及其加速骨中肿瘤生长的能力，2）为了阐明靶向 前列腺癌细胞胞浆细胞增多症引发的信号通路的机制， 免疫抑制和骨中肿瘤生长，以及3）鉴定免疫抑制和骨中肿瘤生长的特异性基因表达特征。 骨髓巨噬细胞/单核细胞在骨转移中的作用。该项目的战略将 包括用选择性抗体精确地靶向巨噬细胞受体Tim-3， 小鼠模型，单细胞RNA-seq分析的独特的转录谱的巨噬细胞肿瘤相关 巨噬细胞，以及Tim-3的信号传导途径与已知的和合成的生化 目标的与其他PO 1项目的相互作用将利用骨细胞衍生因子，脱落酸， 癌细胞的多倍体状态，以确定它们在巨噬细胞 导致了灾难性的肿瘤生长嗜热细胞巨噬细胞在细胞内提供守门活性， 肿瘤微环境，这是特别相关的骨骼转移性病变。瞄准信号 骨髓中巨噬细胞的数量提供了一种新的途径，将有利于患者的设计， 用于治疗前列腺癌骨转移的治疗剂。

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.