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 and express primitive characteristics 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 survial factors such as IGF-1, TGFb etc that support breast cancer cells. Autophagy is an essential part of growth regulation maintenance of homeostasis in multicellular organism. MicroRNAs (miRNAs) are evolutionary conserved; short non-coding regulatory RNAs that post-transcriptionally modulate gene expression of a variety of genes including oncogenes and tumor suppressors, as well as those regulating cell survival and growth. Drosha and Dicer are important enzymes required for miRNA biogenesis. The 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 demonstrating that loss of drosha and dicer function abrogates differentiation in MSCs. The overall goal of this proposal is to understand the role of miRNAs in regulating the survival of tumor-associated stromal cells and in enhancing their supportive function/s towards breast cancer cell growth. The specific hypothesis for this study is the tumor-stroma can survive stressful conditions of the tumor microenvironments by differentially regulating expression of specific miRNAs, and targeting of these miRNAs within the tumor-stroma will abrogate their facilitative effects on breast cancer development and progression. To achieve this goal the following aims are proposed (1) To determine whether a specific miRNA expression profile is associated with the survival of MSCs under stressful conditions in vitro. (2) To investigate the role of stressed stromal cells, and the associated miRNA pathways, in facilitating the stromal supportive functions towards breast cancer cell growth. (3) To delineate the miRNAs that play a role in survival of MSCs and identify those which can be targeted as novel anti-cancer strategies. The experiments proposed here to study the role of miRNA pathway in the stromal cell support 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.

Public Health Relevance

This study will give us insight into the potential role that mesenchymal stem/progenitor cells have in the stromal support of breast cancers. It will also lead to identification of miRNA targets that are involved in the survival of stromal cells under stress and chemotherapeutic drugs. Identification of molecular pathways involved stromal cell survival may lead to identification of new therapeutic targets for resistant breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA151851-02
Application #
8455406
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Jhappan, Chamelli
Project Start
2011-09-09
Project End
2016-07-31
Budget Start
2012-06-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$310,213
Indirect Cost
Name
University of Mississippi Medical Center
Department
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Singh, R; Gupta, S C; Peng, W-X et al. (2016) Regulation of alternative splicing of Bcl-x by BC200 contributes to breast cancer pathogenesis. Cell Death Dis 7:e2262
Whitt, Jason; Vallabhaneni, Krishna C; Penfornis, Patrice et al. (2016) Induced pluripotent stem cell-derived mesenchymal stem cells: A leap toward personalized therapies. Curr Stem Cell Res Ther 11:141-8
Penfornis, Patrice; Vallabhaneni, Krishna C; Whitt, Jason et al. (2016) Extracellular vesicles as carriers of microRNA, proteins and lipids in tumor microenvironment. Int J Cancer 138:14-21
Konala, Vijay Bhaskar Reddy; Mamidi, Murali Krishna; Bhonde, Ramesh et al. (2016) The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell-free regeneration. Cytotherapy 18:13-24
Tanavde, Vivek; Vaz, Candida; Rao, Mahendra S et al. (2015) Research using Mesenchymal Stem/Stromal Cells: quality metric towards developing a reference material. Cytotherapy 17:1169-77
Wu, Kerui; Fukuda, Koji; Xing, Fei et al. (2015) Roles of the cyclooxygenase 2 matrix metalloproteinase 1 pathway in brain metastasis of breast cancer. J Biol Chem 290:9842-54
Vallabhaneni, Krishna C; Penfornis, Patrice; Dhule, Santosh et al. (2015) Extracellular vesicles from bone marrow mesenchymal stem/stromal cells transport tumor regulatory microRNA, proteins, and metabolites. Oncotarget 6:4953-67
Xing, F; Sharma, S; Liu, Y et al. (2015) miR-509 suppresses brain metastasis of breast cancer cells by modulating RhoC and TNF-?. Oncogene 34:4890-900
Tanavde, Vivek; Vemuri, Mohan C; Pochampally, Radhika (2014) Mesenchymal stromal cells: novel methods for characterization, understanding differentiation, and function. Stem Cells Int 2014:630936
Gupta, Subash C; Singh, Ramesh; Pochampally, Radhika et al. (2014) Acidosis promotes invasiveness of breast cancer cells through ROS-AKT-NF-?B pathway. Oncotarget 5:12070-82

Showing the most recent 10 out of 21 publications