MSC Exosomes in Cancer Dormancy

Dormant breast cancers (BRCA) resurge as metastatic disease after a long dormancy period in the bone marrow where cancer cells interact with mesenchymal stem cells (MSC). However, the nature of early interactions between BRCA cells and MSC in the bone marrow microenvironment that facilitate adaptation to a quiescent state remain poorly understood. Here we report that BRCA cells prime MSC to release exosomes containing distinct miRNA contents such as miR-222/223, which in turn promotes quiescence in a subset of cancer cells and confers drug resistance. Building on these results, we developed a novel, non-toxic therapeutic strategy to target dormant BRCA cells based on systemic administration of MSC loaded with antagomiR-222/223. In an immune-deficient mouse model of dormant breast cancer, this therarpy sensitized BRCA cells to carboplatin-based therapy and increased host survival. Overall, our findings illuminate the nature of the regulatory interactions between BRCA cells and MSC in the evolution of tumor dormancy and resurgence in the micrometastatic microenvironment of the bone marrow.

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