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

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...

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Autores principales: Sansone, Pasquale, Savini, Claudia, Kurelac, Ivana, Chang, Qing, Amato, Laura Benedetta, Strillacci, Antonio, Stepanova, Anna, Iommarini, Luisa, Mastroleo, Chiara, Daly, Laura, Galkin, Alexander, Thakur, Basant Kumar, Soplop, Nadine, Uryu, Kunihiro, Hoshino, Ayuko, Norton, Larry, Bonafé, Massimiliano, Cricca, Monica, Gasparre, Giuseppe, Lyden, David, Bromberg, Jacqueline
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664494/
https://www.ncbi.nlm.nih.gov/pubmed/29073103
http://dx.doi.org/10.1073/pnas.1704862114
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author Sansone, Pasquale
Savini, Claudia
Kurelac, Ivana
Chang, Qing
Amato, Laura Benedetta
Strillacci, Antonio
Stepanova, Anna
Iommarini, Luisa
Mastroleo, Chiara
Daly, Laura
Galkin, Alexander
Thakur, Basant Kumar
Soplop, Nadine
Uryu, Kunihiro
Hoshino, Ayuko
Norton, Larry
Bonafé, Massimiliano
Cricca, Monica
Gasparre, Giuseppe
Lyden, David
Bromberg, Jacqueline
author_facet Sansone, Pasquale
Savini, Claudia
Kurelac, Ivana
Chang, Qing
Amato, Laura Benedetta
Strillacci, Antonio
Stepanova, Anna
Iommarini, Luisa
Mastroleo, Chiara
Daly, Laura
Galkin, Alexander
Thakur, Basant Kumar
Soplop, Nadine
Uryu, Kunihiro
Hoshino, Ayuko
Norton, Larry
Bonafé, Massimiliano
Cricca, Monica
Gasparre, Giuseppe
Lyden, David
Bromberg, Jacqueline
author_sort Sansone, Pasquale
collection PubMed
description 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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spelling pubmed-56644942017-11-03 Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer Sansone, Pasquale Savini, Claudia Kurelac, Ivana Chang, Qing Amato, Laura Benedetta Strillacci, Antonio Stepanova, Anna Iommarini, Luisa Mastroleo, Chiara Daly, Laura Galkin, Alexander Thakur, Basant Kumar Soplop, Nadine Uryu, Kunihiro Hoshino, Ayuko Norton, Larry Bonafé, Massimiliano Cricca, Monica Gasparre, Giuseppe Lyden, David Bromberg, Jacqueline Proc Natl Acad Sci U S A PNAS Plus 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. National Academy of Sciences 2017-10-24 2017-10-11 /pmc/articles/PMC5664494/ /pubmed/29073103 http://dx.doi.org/10.1073/pnas.1704862114 Text en Freely available online through the PNAS open access option.
spellingShingle PNAS Plus
Sansone, Pasquale
Savini, Claudia
Kurelac, Ivana
Chang, Qing
Amato, Laura Benedetta
Strillacci, Antonio
Stepanova, Anna
Iommarini, Luisa
Mastroleo, Chiara
Daly, Laura
Galkin, Alexander
Thakur, Basant Kumar
Soplop, Nadine
Uryu, Kunihiro
Hoshino, Ayuko
Norton, Larry
Bonafé, Massimiliano
Cricca, Monica
Gasparre, Giuseppe
Lyden, David
Bromberg, Jacqueline
Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer
title Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer
title_full Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer
title_fullStr Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer
title_full_unstemmed Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer
title_short Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer
title_sort packaging and transfer of mitochondrial dna via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664494/
https://www.ncbi.nlm.nih.gov/pubmed/29073103
http://dx.doi.org/10.1073/pnas.1704862114
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