Role of breast cancer secreted miRNA in brain metastasis

项目总结/摘要 乳腺癌转移到大脑的患病率正在上升，并且由于乳腺癌患者的死亡率越来越高， 有限的治疗选择和高死亡率。因此，有一个巨大的和迫切的需要发展 用于脑归巢转移癌的新的预防和治疗方法。正常的改变功能 转移性小生境中的细胞已被认为是癌症促进转移的重要手段。的 然而，在癌症转移过程中，正常小生境细胞的代谢重编程在很大程度上仍然存在。 未开发的拟议的项目将调查这一独特的方面癌症主机串扰从小说 细胞外miRNA的前景，其功能是将癌症衍生的信号转移到各种类型的细胞中， 最近已经认识到小生境细胞促进癌症生长和转移。miRNA阴性 通过诱导mRNA降解和/或翻译阻断来调节基因表达。这个的目标 这项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，以促进转移，评估潜在的 使用实验模型保护大脑的治疗策略，并评估 这种miRNA作为乳腺癌脑转移的新的基于血液的生物标志物。在目标1中，我们 确定选定的乳腺癌分泌的miRNA在代谢中的作用和作用机制， 脑细胞和组织的重编程，包括通过抑制营养流入的机制。 小鼠模型将用于阐明大脑中能量代谢的改变如何有助于逐步的 乳腺向脑转移的过程在目标2中，我们将评估实验性 作为预防或治疗乳腺癌的新策略的靶向癌症诱导的脑适应的治疗剂 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， 预测或早期诊断乳腺癌患者的脑转移。我们亦会研究 切除的脑转移瘤的标本作为本文鉴定的分子机制的临床证据。 该项目将为我们理解动态传播提供一个新的视角 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的新治疗策略建立理论基础， 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 可能建立循环miRNA作为一种非侵入性生物标志物，以识别具有高风险发展的患者。 脑转移，从而使我们的治疗重点转移到靶向预防脑转移， 转移

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.