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"Facilitation of Breast Cancer Dormancy by Exosomes from Bone Marrow Microenvironmental Mesenchymal Stem and Stromal Cells"

by
Sarah Anne Bliss
Interdisciplinary Biomedical Sciences Program
MBS 2007, Rutgers School of Biomedical Health Science, Newark, NJ
B.S. 2001, Skidmore College, Saratoga Springs, NY


Thesis Advisor: Pranela Rameshwar, Ph.D.
Professor
Department of Medicine

Wednesday, March 18, 2015
9:00 A.M., Medical Science Building, B552


Abstract

The establishment of breast cancer (BC) dormancy could occur years before clinical diagnosis. The bone marrow (BM) has been identified as the source of tumor initiating cells during BC resurgence. This is consistent with the BC stem cells (CSCs) as those with preference for dormancy. This thesis tested the hypothesis that dormancy occurs when two major cells within the BM microenvironment, mesenchymal stem cells (MSCs) and stroma, communicate with BC cells (BCCs) directly through gap junctional intercellular communication (GJIC), and indirectly through exosomes. BCCs and stroma directly communicated with the transfer of miRNAs, such as miR-222/-223 from stroma to reduce CXCL12 and to induce cycling quiescence. In the case of MSCs, when primed with BCCs, the MSCs released exosomes, which were internalized by the BCCs, resulting in cycling quiescence. Application of exosomes from dicer-knockdown MSCs provided evidence that miRNAs were primarily responsible for the cycling transition of the BCCs. Array analyses showed increases in miR-222 within the exosomes of BCC-primed MSCs, thus miR-222 within the dormant BCCs was targeted in vivo by BM-derived MSCs. These studies demonstrated that targeted mice survived significantly longer with no evidence of residual BCCs. In order to understand dormancy further, gene arrays were used to identify genes which could stratify the different BCCs within three major subsets, based on Oct4 expression (Oct4hi, Octmed and Octlow). Three membrane-specific genes, TMEM98, GPR64 and FAT4, showed distinct differences in expression among the BCC subsets, resulting in an expanded working hierarchy of BCCs. The two major subsets, Oct4hi and Oct4low, were shown to release exosomes with distinct miRNA profiles, which could differentially regulate cytokine production in BM stroma. In summary, BCC-primed MSCs release miRNA-containing exosomes, which are internalized by na´ve BCCs to facilitate survival and cycling quiescence. Anti-miR-222 was applied in vivo for targeted therapeutic delivery to reverse dormancy and enable chemosensitization. The development of an expanded hierarchy of BCCs could lead to the identification of biomarkers for treatment responses and to further intervene to reverse dormancy within stroma for eradication. Overall this study could lead to non-toxic methods to treat dormant BCCs in BM and to prevent dormancy.


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