Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer

TLDR

Extracellular vesicles can transfer genetic material, but the mechanisms and roles of this transfer remain largely unknown. The study proposes that mitochondrial DNA is transferred between human cancer cells via extracellular vesicles. The authors discovered that EVs carry complete mitochondrial genomes, transfer mtDNA to oxidative‑phosphorylation‑deficient breast cancer cells to restore metabolism, and that this horizontal transfer in cancer stem‑like cells enhances self‑renewal and confers resistance to hormonal therapy.

Abstract

Significance Increasing evidence suggests that extracellular vesicles (EVs) can transfer genetic material to recipient cells. However, the mechanism and role of this phenomenon are largely unknown. Here we have made a remarkable discovery: EVs can harbor the full mitochondrial genome. These extracellular vesicles can in turn transfer their mtDNA to cells with impaired metabolism, leading to restoration of metabolic activity. We determined that hormonal therapy induces oxidative phosphorylation-deficient breast cancer cells, which can be rescued via the transfer of mtDNA-laden extracellular vesicles. Horizontal transfer of mtDNA occurred in cancer stem-like cells and was associated with increased self-renewal potential of these cells, leading to resistance to hormonal therapy. We propose that mtDNA transfer occurs in human cancer via EVs.