Extracellular vesicle cargo metabolome changes in response to the mesenchymal stromal cell microenvironment and influences cell quiescence and activation in a human breast cancer cell model

Abstract

Breast cancer is the leading cause of cancer mortality in women worldwide and commonly metastasizes to the bone marrow, drastically reducing patient prognosis and survival. In the bone marrow niche, metastatic cells can enter into a dormant state, thereby evading immune surveillance and treatment, and can be reactivated to enter a proliferative state due to poorly understood cues. Mesenchymal stromal cells (MSCs) maintain cells in this niche partly by secreting extracellular matrix and paracrine factors and by responding to regenerative cues. MSCs also produce extracellular vesicles (EVs) that carry a range of cargoes, some of which are implicated in cell signalling. Here, we investigate if the changing metabolic state of MSCs alters the cargoes they package into EVs, and how these changing cargoes act on dormant breast cancer cells (BCCs) using an in vitro BCC spheroid model and a scratch assay to create a regenerative demand on MSCs. Our findings show that EVs produced by standard MSCs contain glycolytic metabolites that maintain BCC dormancy. When MSCs are placed under a regenerative demand and increase their respiration to fuel differentiation, these metabolites disappear from the EV cargo and their absence encourages rapid growth in the BCC spheroids. This work implicates EVs in cancer cell dormancy in the bone marrow niche and indicates that pressures on the niche, such as regeneration, can be a driver of BCC activation.