Mesenchymal Stem Cell-Secreted Extracellular Vesicles Instruct Stepwise Dedifferentiation of Breast Cancer Cells into Dormancy at the Bone Marrow Perivascular Region
In the bone marrow (BM), breast cancer cells (BCC) can survive in dormancy for decades as cancer stem cells (CSC), resurging as tertiary metastasis. The endosteal region where BCCs exist as CSCs poses a challenge to target them, mostly due to the coexistence of endogenous hematopoietic stem cells. This study addresses the early period of dormancy when BCCs enter BM at the perivascular region to begin the transition into CSCs, which we propose as the final step in dormancy. A twostep process comprises the Wnt-b-catenin pathway mediating BCC dedifferentiation into CSCs at the BMperivascular niche. At this site, BCCs responded to two types of mesenchymal stem cell (MSC)-released extracellular vesicles (EV) that may include exosomes. Early released EVs began the transition into cycling quiescence, DNA repair, and reorganization into distinct BCC subsets. After contact with breast cancer, the content of EVs changed (primed) to complete dedifferentiation into a more homogeneous population with CSC properties. BCC progenitors (Oct4alo), which are distant from CSCs in a hierarchical stratification, were sensitive to MSC EVs. Despite CSC function, Oct4alo BCCs expressed multipotent pathways similar to CSCs. Oct4alo BCCs dedifferentiated and colocalized with MSCs (murine and human BM) in vivo. Overall, these findings elucidate a mechanism of early dormancy at the BM perivascular region and provide evidence of epigenome reorganization as a potential new therapy for breast cancer.
Digital Object Identifier (DOI)
Sandiford, O. A., Donnelly, R. J., El-Far, M. H., Burgmeyer, L. M., Sinha, G., Pamarthi, S. H., Sherman, L. S., Ferrer, A. I., DeVore, D. E., Patel, S. A., Naaldijk, Y., Alonso, S., Barak, P., Bryan, M., Ponzio, N. M., Narayanan, R., Etchegaray, J. P., Kumar, R., & Rameshwar, P. (2021). Mesenchymal Stem Cell-Secreted Extracellular Vesicles Instruct Stepwise Dedifferentiation of Breast Cancer Cells into Dormancy at the Bone Marrow Perivascular Region. Cancer research, 81(6), 1567–1582. https://doi.org/10.1158/0008-5472.CAN-20-2434