Mitochondrial lateral transfer during metastasis

转移过程中的线粒体横向转移

• 批准号: 10559498
• 负责人: Minna Roh
• 金额: $ 34.19万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559498
• 关键词: Affect; Automobile Driving; Behavior; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cell Communication; Cell Proliferation; Cell physiology; Cells; Coculture Techniques; Collaborations; Communication; Communities; Cues; Cytoplasm; Darkness; Development; Electron Microscopy; Event; Exhibits; Future; Generations; Global Change; Goals; Homeostasis; Human; Immune; Immune system; Immunotherapy; In Vitro; Injections; Lateral; Macrophage; Malignant Neoplasms; Mediating; Melanoma Cell; Metabolic; Metastatic Melanoma; Mitochondria; Morphology; Neoplasm Metastasis; Organelles; PIK3CG gene; Pathway interactions; Phenotype; Play; Population; Positioning Attribute; Primary Neoplasm; Process; Proliferating; Reactive Inhibition; Reactive Oxygen Species; Reporting; Resolution; Respiration; Role; Side; Signal Pathway; Signal Transduction; Signaling Molecule; Solid Neoplasm; Source; Stromal Cells; Structure; System; Testing; Tumor-associated macrophages; Utah; Visualization; Zebrafish; cancer cell; carcinogenesis; cell behavior; experimental study; extracellular; imaging approach; in vivo; knock-down; light microscopy; malignant breast neoplasm; melanoma; mouse model; neoplastic cell; receptor; response; tumor; tumor microenvironment; tumorigenic

Project Summary Macrophages play paradoxical roles in cancer: They can be tumoricidal, but in many cancers, macrophages promote metastasis. There has been growing evidence that macrophages can modulate cell behavior via unconventional cell contact-mediated communication in development and homeostasis. We have recently extended these paradigms by discovering that macrophages can also engage in unconventional cell contact- mediated communication with tumor cells within the tumor microenvironment, and that these interactions contribute to metastasis. By visualizing and manipulating highly migratory melanoma cells and their microenvironment in vivo, we unexpectedly found that tumor-associated macrophages transfer cytoplasmic contents to melanoma cells in a cell contact-dependent manner. Remarkably, 70-80% of melanoma cells that received macrophage cytoplasm disseminated from the primary tumor in both zebrafish and murine models. We are now ideally positioned to identify key component(s) that are transferred from macrophages to tumor cells for metastasis, and how this transfer occurs. Mitochondria are dynamic organelles that perform a variety of essential cellular functions. Mitochondria have been shown to transfer to tumor cells in vivo, restoring their respiration and ability to form tumors. While these elegant “proof of principle” studies demonstrated that mitochondrial lateral transfer can occur in the tumor microenvironment, the donor stromal cell(s) were not identified, the transfer mechanism was not defined, and the fates and functions of mitochondria in tumor cells were not characterized. Excitingly, we have found that primary human macrophages can transfer mitochondria to human breast cancer cells and melanoma cells, two cancers in which macrophages have been shown to play a pro-tumorigenic role. Tumor cells that receive macrophage mitochondria either by spontaneous mitochondrial transfer in coculture, or by direct injection of purified macrophage mitochondria, exhibit increased proliferation. Surprisingly, we find that after mitochondrial transfer occurs, the transferred mitochondria remain as a spatially distinct population from the host mitochondrial network. Furthermore, we found that high levels of local reactive oxygen species accumulate at transferred mitochondria, suggesting an intriguing hypothesis that transferred mitochondria may provide a signal to tumor cells, rather than providing excess mitochondrial function as has been previously described. To test this hypothesis, we propose to: (Aim 1) Understand how mitochondria dynamically reorganize for mitochondrial transfer to tumor cells and (Aim 2) Determine how mitochondrial transfer mechanistically induces cancer cell proliferation. Taken together, these experiments will reveal whether macrophage mitochondrial transfer can instruct breast cancer and melanoma cells to become more robust and metastatic. Our goals are to define how immune cells function in the tumor microenvironment, and to provide a basis for developing future immunotherapies that limit metastasis.

项目概要 巨噬细胞在癌症中扮演着矛盾的角色：它们可以杀肿瘤，但在许多癌症中，巨噬细胞 越来越多的证据表明巨噬细胞可以通过调节细胞行为。 我们最近研究了发育和稳态中非常规细胞接触介导的通讯。 通过发现巨噬细胞也可以参与非常规的细胞接触，扩展了这些范式- 介导与肿瘤微环境中肿瘤细胞的通讯，并且这些相互作用 通过观察和操纵高度迁移的黑色素瘤细胞及其来促进转移。 在体内微环境中，我们意外地发现肿瘤相关巨噬细胞转移细胞质 值得注意的是，70-80% 的黑色素瘤细胞以细胞接触依赖性方式发生变化。 在斑马鱼和小鼠模型中接受了从原发肿瘤传播的巨噬细胞细胞质。 我们现在处于理想的位置，可以识别从巨噬细胞转移到肿瘤的关键成分 细胞进行转移，以及这种转移是如何发生的。线粒体是执行多种任务的动态细胞器。 线粒体已被证明可以转移到体内的肿瘤细胞，恢复其功能。 虽然这些优雅的“原理证明”研究表明，呼吸和形成肿瘤的能力。 线粒体横向转移可以发生在肿瘤微环境中，而供体基质细胞则不然 已确定，转移机制尚未明确，肿瘤细胞中线粒体的命运和功能 令人兴奋的是，我们发现初级人类巨噬细胞可以转移线粒体。 人类乳腺癌细胞和黑色素瘤细胞，这两种癌症中巨噬细胞已被证明 通过自发接收巨噬细胞线粒体发挥促肿瘤作用。 共培养中的线粒体转移，或通过直接注射纯化的巨噬细胞线粒体，表现出增加 令人惊讶的是，我们发现线粒体转移发生后，转移的线粒体仍然存在。 作为与宿主线粒体网络在空间上不同的群体，我们发现高水平的线粒体。 局部活性氧在转移的线粒体处积聚，这提出了一个有趣的假设： 转移的线粒体可以向肿瘤细胞提供信号，而不是提供过量的线粒体 为了检验这个假设，我们建议：（目标 1）了解如何实现。 线粒体动态重组以将线粒体转移至肿瘤细胞并（目标 2）确定如何 线粒体转移机械地诱导癌细胞增殖。 揭示巨噬细胞线粒体转移是否可以指导乳腺癌和黑色素瘤细胞变成 我们的目标是确定免疫细胞在肿瘤微环境中的功能， 并为开发未来限制转移的免疫疗法提供基础。