Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer Journal Article
| Authors: | Sansone, P.; Savini, C.; Kurelac, I.; Chang, Q.; Amato, L. B.; Strillacci, A.; Stepanova, A.; Iommarini, L.; Mastroleo, C.; Daly, L.; Galkin, A.; Thakur, B. K.; Soplop, N.; Uryu, K.; Hoshinob, A.; Norton, L.; Bonafé, M.; Cricca, M.; Gasparre, G.; Lyden, D.; Bromberg, J. |
| Article Title: | Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer |
| Abstract: | 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 genomicmtDNA as amediator of this phenotype. Specifically, the treatment of hormone therapy (HT)-naive cells or HT-treated metabolically dormant populations with CAF-derived mtDNAhi 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. |
| Keywords: | human cell; nonhuman; mouse; metastasis; breast cancer; animal experiment; animal model; tumor xenograft; cancer resistance; cancer hormone therapy; cancer stem cell; estrogen receptor; oxidative phosphorylation; fulvestrant; mitochondrial dna; deoxyribonuclease; cancer associated fibroblast; exosome; mitochondrial genome; sanger sequencing; human; priority journal; article; stem cell self-renewal; bone marrow stroma cell |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 114 |
| Issue: | 43 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2017-10-24 |
| Start Page: | E9066 |
| End Page: | E9075 |
| Language: | English |
| DOI: | 10.1073/pnas.1704862114 |
| PROVIDER: | scopus |
| PMCID: | PMC5664494 |
| PUBMED: | 29073103 |
| DOI/URL: | |
| Notes: | Erratum issued, see DOI: 10.1073/pnas.1718630114 -- Article -- Export Date: 4 December 2017 -- Source: Scopus |
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