Mitochondrial lateral transfer during metastasis

转移过程中的线粒体横向转移

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要巨噬细胞在癌症中扮演矛盾的角色：它们可能是肿瘤性的，但在许多癌症中，巨噬细胞促进转移。越来越多的证据表明巨噬细胞可以通过非常规细胞接触介导的发展和稳态中的交流。我们最近有通过发现巨噬细胞也可以参与非常规细胞接触来扩展这些范例 - 介导了与肿瘤微环境内肿瘤细胞的通讯，这些相互作用有助于转移。通过可视化和操纵高度迁移的黑色素瘤细胞及其微环境在体内，我们意外地发现肿瘤相关的巨噬细胞转移细胞质以细胞接触依赖性方式对黑色素瘤细胞的含量。值得注意的是，有70-80％的黑色素瘤细胞在斑马鱼和鼠模型中，接受了从原发性肿瘤中传播的巨噬细胞细胞质。现在，我们处于理想状态，可以识别从巨噬细胞转移到肿瘤的关键成分转移的细胞，以及这种转移的发生方式。线粒体是执行多样性的动态细胞器必需的细胞功能。线粒体已显示在体内转移到肿瘤细胞，恢复其呼吸和形成肿瘤的能力。尽管这些优雅的“原则证明”研究表明线粒体侧向转移可能发生在肿瘤微环境中，供体基质细胞不是确定，未定义转移机制，线粒体在肿瘤细胞中的命运和功能没有表征。令人兴奋的是，我们发现原发性巨噬细胞可以转移线粒体对于人类乳腺癌细胞和黑色素瘤细胞，两种巨噬细胞已证明的癌症扮演亲瘤的角色。通过赞助接收巨噬细胞线粒体的肿瘤细胞线粒体转移在共培养中或直接注射纯化的巨噬细胞线粒体，暴露于增殖。令人惊讶的是，我们发现线粒体转移发生后，将线粒体保留作为与宿主线粒体网络的空间不同人群。此外，我们发现高水平局部活性氧在转移的线粒体上积聚，这表明一个有趣的假设是转移的线粒体可能为肿瘤细胞提供信号，而不是提供过多的线粒体正如先前描述的那样。为了检验这一假设，我们建议：（目标1）了解如何线粒体动态地重组线粒体转移至肿瘤细胞，（AIM 2）确定如何线粒体转移机械地诱导癌细胞增殖。两者一起，这些实验将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成为更健壮和转移。我们的目标是定义免疫细胞如何在肿瘤微环境中起作用，并为开发限制转移的未来免疫疗法提供基础。