Role of breast cancer secreted miRNA in brain metastasis

项目摘要/摘要 乳腺癌脑转移的发病率正在上升，对患者的致命性威胁越来越大，这是由于 治疗选择非常有限，死亡率很高。因此，迫切需要发展。 脑归巢转移癌的新预防和治疗方法。正常的功能改变 转移生态位中的细胞已被认为是癌症促进转移的重要手段。这个 然而，在癌症转移期间，正常的壁龛细胞的代谢重新编程在很大程度上仍然存在。 未被开发的。拟议中的项目将调查小说中癌症-宿主相声的这一独特方面。 细胞外miRNA在向多种类型的肿瘤细胞传递肿瘤信号中的作用 利基细胞促进肿瘤生长和转移的作用最近已被认识到。MiRNA为阴性 通过诱导信使核糖核酸降解和/或翻译阻断来调节基因表达。这样做的目的是 研究旨在确定癌细胞分泌的miRNA重新编程能量的机制 脑细胞(神经元和星形胶质细胞)的代谢促进转移，以评估潜力 使用实验模型保护大脑的治疗策略，并评估 这种miRNA作为一种新的基于血液的生物标志物用于乳腺癌脑转移。在目标1中，我们将 确定选定的乳腺癌分泌的miRNA在代谢中的作用和作用机制 脑细胞和组织的重新编程，包括通过抑制营养物质流入的机制。 小鼠模型将被用来阐明大脑中能量新陈代谢的改变如何有助于逐步 乳房到脑转移的过程。在目标2中，我们将评估实验的有益效果 以癌症诱导的脑适应为靶向的治疗药物是预防或治疗乳腺癌的新策略 癌症脑转移。在目标3中，我们将评估循环miRNA作为临床生物标志物的潜力。 乳腺癌患者脑转移的预测或早期诊断。我们还将调查 切除的脑转移瘤标本为临床证据，在此确定了分子机制。 所提出的项目将为我们理解动态交流提供一个新的视角 癌症和宿主之间的关系以及脑转移发展的复杂机制。它 可能为预防或治疗脑转移癌和脑转移癌的新治疗策略奠定基础 减轻癌症对大脑功能的不利影响，这是我们的长期目标。重要的是，我们的研究 可以建立循环miRNA作为一种非侵入性生物标志物来识别高危患者 脑转移，从而使我们的治疗重点转移到针对大脑的预防 转移瘤。

PROJECT SUMMARY/ABSTRACT Breast cancer metastasis to the brain is rising in prevalence and is an increasingly lethal threat to patients due to the very limited treatment options and high mortality. Therefore, there is a great and urgent need to develop novel preventive and therapeutic treatments for brain-homing metastatic cancer. Altered function of normal cells in a metastatic niche has been recognized as an important means for cancer to facilitate metastasis. The metabolic reprogramming of normal niche cells during cancer metastasis, however, remains largely unexplored. The proposed project will investigate this unique aspect of cancer–host crosstalk from the novel perspective of extracellular miRNA, whose function in transferring cancer-derived signals to various types of niche cells to facilitate cancer growth and metastasis has been recently recognized. MiRNA negatively regulates gene expression through inducing mRNA degradation and/or translation blockade. The goals of this study are to identify the mechanism by which cancer cell-secreted miRNA reprograms the energy metabolism of brain cells (neurons and astrocytes) to promote metastasis, to assess potential therapeutic strategies to protect the brain using experimental models, and to evaluate the potential of such miRNA as a novel blood-based biomarker for breast cancer brain metastasis. In Aim 1, we will determine the effects and acting mechanism of selected breast cancer-secreted miRNA in the metabolic reprogramming of brain cells and tissues, including a mechanism through suppression of nutrient influxes. Mouse models will be used to elucidate how altered energy metabolism in the brain contributes to the stepwise process of breast-to-brain metastasis. In Aim 2, we will assess the beneficial effects of experimental therapeutics targeting cancer-induced adaptation of the brain as novel strategies to prevent or treat breast cancer brain metastasis. In Aim 3, we will evaluate the potential of circulating miRNA as a clinical biomarker for the prediction or early diagnosis of brain metastasis in breast cancer patients. We will also investigate specimens of resected brain metastases for clinical evidence of the herein identified molecular mechanism. The proposed project will provide a novel perspective to our understandings of the dynamic communication between cancer and host and of the complex mechanisms underlying the development of brain metastases. It may establish rationales for novel therapeutic strategies to prevent or treat brain-metastasizing cancer and alleviate cancer’s adverse effects on brain function, which is our long-term objective. Importantly, our study may establish circulating miRNA as a non-invasive biomarker to identify patients with a high risk of developing brain metastases, thereby enabling a shift of our therapeutic focus to targeting the prevention of brain metastases.