期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 43, 页码 E9066-E9075出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1704862114
关键词
exosomes; mitochondrial DNA; cancer stem cells; hormonal therapy; metastasis
资金
- US Department of Defense [W81XWH-10-1-1013, W81XWH-13-1-0425, W81XWH-13-1-0427]
- MSKCC [P30 CA008748]
- Charles and Marjorie Holloway Foundation
- Sussman Family Fund
- Lerner Foundation
- Beth C. Tortolani Foundation
- National Cancer Institute [CA169538]
- Manning Foundation
- Paduano Foundation
- Champalimaud Foundation
- Mary Kay Foundation
- Malcolm Hewitt Weiner Foundation
- Rapp Foundation
- American Hellenic Educational Progressive Association 5th District Cancer Research Foundation
- Marco Polo Fellowship Universita di Bologna
- Italian Association for Cancer Research [IG14242_JANEUTICS]
- Italian Ministry of Health [GR-2013-02356666]
- EU People Marie Curie Action, Mitochondrial European Educational Training [317433]
- Medical Research Council UK [MR/L007339/1]
- Palloti Legacy
- MRC [MR/L007339/1] Funding Source: UKRI
- Medical Research Council [MR/L007339/1] Funding Source: researchfish
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(hi) 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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