Investigating macrophage-to-tumor mitochondrial transfer

项目摘要 肿瘤转移是癌症相关死亡的主要原因，但可以预防这种恶性表型。 继续躲避科学调查人员。为了了解哪些因素会导致恶性肿瘤 肿瘤的行为、微环境已成为研究的热点和肿瘤侵袭的巨噬细胞 已被证明是导致预后不良的原因之一。我们的目标是更好地了解巨噬细胞-肿瘤细胞 相互作用促进侵袭性肿瘤表型。在这项工作中，我们证明了巨噬细胞转移 大量细胞质直接进入肿瘤细胞，受体细胞在体外表现出更强的迁移能力 在体内传播。最近，我们开始确定在这些相互作用中转移了哪些物质。 利用原代人巨噬细胞和人乳腺癌细胞，我们观察到巨噬细胞转移 线粒体到乳腺癌细胞。重要的是，接受巨噬细胞线粒体的癌细胞也 表现出增强的细胞增殖，这是转移级联的关键步骤。然后我们的目标是确定 巨噬细胞极化是否影响线粒体转移并观察促肿瘤的M2样蛋白 巨噬细胞表现出增强的线粒体转移率。由于Notch信令已被证明 影响巨噬细胞极化，我们着手确定Notch信号是否也影响传递 发现抑制Notch信号导致巨噬细胞比率增加 线粒体转移，促进M2样巨噬细胞表型。这些发现阐明了 建议研究巨噬细胞至肿瘤的线粒体转移。通过利用体外和体内模型，我们 将研究原代小鼠促肿瘤相关巨噬细胞的线粒体转移 确定它们的线粒体动力学如何影响线粒体转移。此外，我们将确定 Notch信号如何影响这些过程和随后的线粒体转移。给出了那个缺口 目前，信号转导抑制剂正处于治疗乳腺癌的临床研究中，这些数据显示了 诱人的前提：如果抑制Notch信号促进线粒体转移和随后的肿瘤 扩散，在这种治疗的背景下，哪些基本生物学可能被忽视？在这项提议中，我们将转移 从转移后肿瘤细胞表型到转移前巨噬细胞生物学的焦点及其如何 表型可能影响线粒体的转移。重要的是，拟议的重点是移植前生物学 线粒体供体细胞的特性以及哪些动力学特性促进了线粒体的转移 调查过了。我们的工作将阐明目前尚未被认识的巨噬细胞相关机制 致瘤性。通过深入了解基础巨噬细胞生物学和Notch信号如何影响 巨噬细胞到肿瘤的线粒体转移，这项工作将有助于指导临床努力抑制Notch和PRIME 巨噬细胞-肿瘤相互作用防止线粒体转移和阻碍肿瘤生长的未来研究 转移性级联。

Project Summary Tumor metastasis is the leading cause of cancer related mortalities, yet preventing this malignant phenotype continues to elude scientific investigators. In efforts to understand what factors promote malignant cancer behavior, the tumor microenvironment has become an intense focus of study and tumor-infiltrating macrophages have been shown to contribute to poor prognosis. We aimed to better understand how macrophage-tumor cell interactions promote aggressive tumor phenotypes. In this effort, we demonstrated that macrophages transfer bulk cytoplasmic material directly to tumor cells and that recipient cells exhibit enhanced migration in vitro and dissemination in vivo. Recently, we set out to determine what material is transferred during these interactions. Using primary human macrophages and human breast cancer cells, we observed that macrophages transfer mitochondria to breast cancer cells. Importantly, cancer cells that received macrophage mitochondria also exhibited enhanced cell proliferation, a critical step of the metastatic cascade. We then aimed to determine whether macrophage polarization influenced mitochondrial transfer and observed that pro-tumorigenic M2-like macrophages exhibit enhanced rates of mitochondrial transfer. Since Notch signaling has been shown to influence macrophage polarization, we set out to determine whether Notch signaling also influences the transfer of mitochondria and found that the inhibition of Notch signaling resulted in increased rates of macrophage mitochondrial transfer and promoted M2-like macrophage phenotypes. These findings have set forth the proposed investigation of macrophage-to-tumor mitochondrial transfer. By utilizing in vitro and in vivo models we will investigate mitochondrial transfer from primary mouse pro-tumorigenic Tumor Associated Macrophages and determine how their mitochondrial dynamics influence mitochondrial transfer. Furthermore, we will determine how Notch signaling influences these processes and subsequent mitochondrial transfer. Given that Notch signaling inhibitors are currently under clinical pursuit for the treatment of breast cancer, these data present an enticing premise: if inhibition of Notch signaling promotes mitochondrial transfer and subsequent tumor proliferation, what basic biology may be overlooked in the context of this treatment? In this proposal we will shift the focus from post-transfer tumor cell phenotypes to pre-transfer macrophage biology and how these phenotypes may be influencing mitochondrial transfer. Importantly, the proposed focus on pre-transfer biology of the mitochondrial ‘donor’ cell and what dynamic properties promote mitochondrial transfer have not been investigated. Our work will illuminate a currently unappreciated mechanism of macrophage-associated tumorigenicity. By providing insights to how foundational macrophage biology and Notch signaling influence macrophage-to-tumor mitochondrial transfer, this work will help guide clinical efforts of Notch inhibition and prime future investigations of macrophage-tumor interactions to prevent mitochondrial transfer and hinder the metastatic cascade.