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

TitlePackaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer.
Publication TypeJournal Article
Year of Publication2017
AuthorsSansone P, Savini C, Kurelac I, Chang Q, Amato LBenedetta, Strillacci A, Stepanova A, Iommarini L, Mastroleo C, Daly LA, Galkin A, Thakur BKumar, Soplop N, Uryu K, Hoshino A, Norton L, Bonafé M, Cricca M, Gasparre G, Lyden DC, Bromberg JF
JournalProc Natl Acad Sci U S A
Date Published2017 10 24
KeywordsBreast Neoplasms, Cell Line, Tumor, DNA, Mitochondrial, Drug Resistance, Neoplasm, Exosomes, Female, Fibroblasts, Gene Transfer, Horizontal, Genome, Mitochondrial, Humans, MCF-7 Cells, NADH Dehydrogenase, Oxidative Phosphorylation, Receptors, Estrogen, Xenograft Model Antitumor Assays

The horizontal transfer of mtDNA and its role in mediating resistance to therapy and an exit from dormancy have never been investigated. Here we identified the full mitochondrial genome in circulating extracellular vesicles (EVs) from patients with hormonal therapy-resistant (HTR) metastatic breast cancer. We generated xenograft models of HTR metastatic disease characterized by EVs in the peripheral circulation containing mtDNA. Moreover, these human HTR cells had acquired host-derived (murine) mtDNA promoting estrogen receptor-independent oxidative phosphorylation (OXPHOS). Functional studies identified cancer-associated fibroblast (CAF)-derived EVs (from patients and xenograft models) laden with whole genomic mtDNA as a mediator of this phenotype. Specifically, the treatment of hormone therapy (HT)-naive cells or HT-treated metabolically dormant populations with CAF-derived mtDNA EVs promoted an escape from metabolic quiescence and HTR disease both in vitro and in vivo. Moreover, this phenotype was associated with the acquisition of EV mtDNA, especially in cancer stem-like cells, expression of EV mtRNA, and restoration of OXPHOS. In summary, we have demonstrated that the horizontal transfer of mtDNA from EVs acts as an oncogenic signal promoting an exit from dormancy of therapy-induced cancer stem-like cells and leading to endocrine therapy resistance in OXPHOS-dependent breast cancer.

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Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID29073103
PubMed Central IDPMC5664494
Grant ListMR/L007339/1 / / Medical Research Council / United Kingdom
P30 CA008748 / CA / NCI NIH HHS / United States
U01 CA169538 / CA / NCI NIH HHS / United States

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