(PQ5) Microenvironmental Regulation of Mitochondrial Heterogeneity in Cancer Metastasis

摘要 转移占所有癌症死亡的90%以上。控制这些变化的基本机制 转移级联仍然知之甚少。线粒体代谢已成为一个关键组成部分， 和癌症转移的潜在主要调节因子，并且已经观察到线粒体活性增加 在循环肿瘤细胞中。我们之前已经开发了一种微模式肿瘤基质测定（µTSA）， 概括了乳腺癌中肿瘤-间质界面的空间分辨细胞串扰，我们最近 发现在肿瘤-间质界面附近诱导异质性线粒体表型。我们 中心假设是肿瘤微环境中的物理化学相互作用引起异质性， 线粒体和代谢活动，导致不同的侵袭性和转移性表型。这里我们将 开发基于µ TSA的肿瘤模型，以模拟关键的肿瘤微环境线索，并评估其作用 在调节线粒体异质性和转移潜力在体外和体内。拟定研究 将不仅提供线粒体微环境决定因素的系统理解， 异质性，而且线粒体和转移表型之间的机制关系。的 洞察力和开发的平台将推进癌症转移的靶向治疗，并使广泛的 一系列领域包括癌症代谢、干细胞生物学、生物标志物发现和药物筛选。

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.