miRNA-mediated Stromal Cell Survival under Stress Supports Breast Cancer Growth

描述(申请人提供)：多潜能间充质干细胞(MSCs)在治疗人类退行性疾病和损伤方面具有巨大的潜力。最近有关乳腺癌间质生物学的研究表明，间充质干细胞(MSCs)为乳腺癌提供支持间质。然而，在我们对基质细胞在通常在实体瘤中观察到的应激条件下的生存机制的理解上有很大的差距，例如缺氧或营养缺乏。目前可用的治疗策略大多只针对癌细胞，而不是肿瘤相关的间质。事实上，更详细地了解MSC存活所涉及的分子机制以及由此产生的间质支持功能，对于改进乳腺癌治疗靶点的设计和选择至关重要。在这项研究中，在血清剥夺中存活的MSC亚群的特性将被用作模型，以了解基质细胞在乳腺癌中的作用，特别是在缺氧或营养剥夺等不利条件下。去血清骨髓间充质干细胞(SD-MSCs)通过自噬存活并分泌支持乳腺癌细胞的生存因子如胰岛素样生长因子-1、转化生长因子�等。MicroRNAs(MiRNAs)通过与同源靶标mRNA结合来发挥作用，并促进其特异性降解。我们的初步数据揭示了一种将SD-MSC存活与miRNA调控联系起来的新机制，除了对miRNA的细胞内差异调控外，我们还显示了SD-MSCs的分泌体中miRNA的表达，其中包括外体。这个项目的总体目标是了解MSCs在实体瘤，特别是乳腺癌中的间质支持特性。本研究的特定假设是，我们假设肿瘤间质中的MSCs通过差异调节特定的miRNAs的表达，在肿瘤微环境的营养缺乏和低氧条件下存活，从而靶向消除它们对乳腺癌发生和发展的促进作用。为了实现这一目标，提出了以下目标：(1)确定miRNA介导的调控基质细胞在血清剥夺和缺氧条件下存活的关键机制。(2)了解胞外途径在调控MSCs的肿瘤支持特性中的作用。(3)寻找在原发肿瘤模型中可作为抗癌新策略靶点的特异性miRNAs。研究miRNA途径在使用原代肿瘤起始细胞和MSCs支持间质细胞中的作用，对于了解间质细胞如何在不利条件下存活并支持其周围的肿瘤细胞具有重要意义。此外，还将确定消灭存活的基质细胞的新的治疗靶点。

DESCRIPTION (provided by applicant): Multipotential Mesenchymal Stromal cells (MSCs) hold great potential for treating human degenerative diseases and injuries. Recent studies regarding the biology of breast cancer stroma indicate that mesenchymal stem cells (MSCs) provide the supportive stroma for breast tumors. However, there is a significant gap in our understanding of the survival mechanisms used by stromal cells under stressful conditions normally observed within solid tumors, such as hypoxia or nutrient deprivation. Most of the currently available therapeutic strategies only target the cancer cells and not the tumor-associated stroma. Indeed, a more detailed understanding of the molecular mechanisms involved in MSC survival and the resultant stromal supportive functions, is essential for improving the design and selection of therapeutic targets against breast cancer. In this study, properties of a MSC subpopulation that survive serum deprivation will be used as model to understand role of stromal cells in breast cancers especially during adverse conditions such as hypoxia or nutrient deprivation. The serum deprived MSCs (SD-MSCs) utilize autophagy to survive and secrete survival factors such as IGF-1, TGF� etc that support breast cancer cells. The microRNAs (miRNAs) function by binding to a cognate targets mRNA and facilitates their specific degradation. Our preliminary data uncovered a novel mechanism of linking SD-MSC survival to miRNA regulation, in addition to intracellular differential regulation of miRNA we show the miRNA expression the secretome of SD-MSCs that includes exosomes. The overall goal of this project is to understand the stromal supportive properties of MSCs in solid tumors specifically breast cancers. The specific hypothesis for this study is we hypothesize that MSCs in the tumor stroma survive nutrient deprived and hypoxic conditions of the tumor microenvironment by differentially regulating the expression of specific miRNAs, which can be targeted to abrogate their facilitative effects on breast cancer development and progression. To achieve this goal the following aims are proposed (1) Determine the key miRNA mediated mechanism governing survival of stromal cells in response to serum deprivation and hypoxia. (2) Understand the role of exosomal pathway in governing the tumor supportive properties of MSCs. (3 To identify the specific miRNAs that can be targeted as novel anti-cancer strategies in primary tumor models. The experiments proposed here to study the role of miRNA pathway in the stromal cell support using primary tumor initiating cells and MSCs will be important to understand how stromal cells survive under adverse conditions and support the tumor cells surrounding them. In addition, novel therapeutic targets to abrogate stromal cell survial will be indentified.