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

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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.