(PQ5) Microenvironmental Regulation of Mitochondrial Heterogeneity in Cancer Metastasis

摘要 转移占所有癌症死亡的90%以上。控制的基本机制 转移的级联效应仍然知之甚少。线粒体新陈代谢已成为一个关键组成部分 和潜在的癌症转移的主要调节因子，并观察到线粒体活性的增加 在循环中的肿瘤细胞中。我们之前已经开发了一种微图案化肿瘤间质分析(µTSA)来 概述乳腺癌肿瘤-间质交界处的空间分辨细胞交叉对话，我们最近 发现在肿瘤-间质界面附近诱导了不同的线粒体表型。我们的 中心假说是肿瘤微环境中的物理化学作用导致异质性。 线粒体和代谢活动，导致不同的侵袭性和转移性表型。在这里，我们将 开发基于µTSA的肿瘤模型来模拟关键的肿瘤微环境线索，并评估它们的作用 在体外和体内调节线粒体的异质性和转移潜能。建议进行的研究 将不仅提供对线粒体微环境决定因素的系统了解 异质性，以及线粒体和转移表型之间的机制关系。这个 洞察力和开发的平台将推动癌症转移的靶向治疗，并使广泛的人受益 包括癌症代谢、干细胞生物学、生物标记物发现和药物筛选在内的一系列领域。

ABSTRACT Metastasis accounts for more than 90% of all cancer deaths. The underlying mechanisms controlling the metastatic cascades are still poorly understood. Mitochondrial metabolism has emerged as a key component and potential master regulator of cancer metastasis, and increased mitochondrial activities have been observed in circulating tumor cells. We have previously developed a micropatterned tumor-stromal assay (µTSA) to recapitulate spatially-resolved cellular cross-talks at the tumor-stroma interface in breast cancer, and we recently discovered that heterogeneous mitochondrial phenotypes are induced near the tumor-stroma interface. Our central hypothesis is that physicochemical interactions in tumor microenvironment give rise to heterogeneous mitochondrial and metabolic activities, leading to differential invasive and metastatic phenotypes. Here we will develop µTSA-based tumor models to mimic critical tumor microenvironmental cues, and to evaluate their roles in regulating mitochondrial heterogeneity and metastatic potential both in vitro and in vivo. The proposed study will provide not only a systems understanding of the microenvironmental determinants of mitochondrial heterogeneity, but also the mechanistic relationship between mitochondrial and metastatic phenotypes. The insights and developed platform will advance targeted therapeutics for cancer metastasis, and benefit a broad range of areas including cancer metabolism, stem cell biology, biomarker discovery, and drug screening.