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

Abstract

SignificanceIncreasing 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.

Blood contains circulating cell‐free respiratory competent mitochondria

“…All cell‐free mitochondria in human plasma or cell culture media supernatant as observed by EM were not surrounded by a bi‐ or multi‐layer phospholipid membrane. A few studies suggested that mitochondrial DNA could be encapsulated in extracellular vesicles such as exosomes and microvesicles, and act as efficient messengers in many biological systems . One can speculate that the previously described biological effect of cell‐free mitochondrial DNA enriched micro‐particles could, as well, be performed by cell‐free intact mitochondria as their presence in blood was not known before the study of Boudreau et al and Puhm et al .…”

Non-coding RNAs: long non-coding RNAs and microRNAs in endocrine-related cancers

“…Interestingly, a recent study reported that EVs isolated from BCa patients with metastatic disease, and whose initial tumor had been ERα+/PR+/HER2-, contained mtRNA from cancerassociated fibroblasts (CAFs) (Sansone, et al 2017). Xenograft transplantation studies in immunocompromised mice demonstrated that transfer of mtDNA from CAFs contributed to resistance to fulvestrant in vivo.…”

Tumor‐derived exosomes (TDEs): How to avoid the sting in the tail

“…Nuclear envelope instability, particularly in micronuclei arising from chromosome breakage or mitotic errors, represents a likely candidate mechanism for the increase in cytosolic release of nuclear DNA in senescent or cancer cells, but the mechanism(s) responsible for packaging this material into exosomes is not clear, nor whether there is differential regulation of this process upon cell senescence or cancer development and progression. While this study did not detect mitochondrial DNA in during its analysis of exosome DNA content from senescent cells, another study found that tumor‐associated exosomes can package significant amounts of mitochondrial DNA, which could rescue recipient cancer cells from metabolic dormancy by stimulating oxidative phosphorylation . Notably, this study also found that exosomes isolated from cancer‐associated fibroblasts preferentially transferred mitochondrial DNA to cancer stem cells (CSCs) relative to non‐CSC‐like populations to increase their potential for self‐renewal.…”