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

被引：656

作者：

Sansone, Pasquale ^{[1
,2
]}

Savini, Claudia ^{[1
,3
,4
]}

Kurelac, Ivana ^{[5
]}

Chang, Qing ^{[1
]}

Amato, Laura Benedetta ^{[5
]}

Strillacci, Antonio ^{[1
,6
]}

Stepanova, Anna ^{[7
]}

Iommarini, Luisa ^{[8
]}

Mastroleo, Chiara ^{[1
]}

Daly, Laura ^{[1
]}

Galkin, Alexander ^{[7
,9
]}

Thakur, Basant Kumar ^{[2
,10
,12
]}

Soplop, Nadine ^{[11
]}

Uryu, Kunihiro ^{[11
]}

Hoshinob, Ayuko ^{[2
]}

Norton, Larry ^{[1
]}

Bonafe, Massimiliano ^{[3
,4
]}

Cricca, Monica ^{[3
]}

Gasparre, Giuseppe ^{[5
]}

Lyden, David ^{[2
,10
]}

Bromberg, Jacqueline ^{[1
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[2] Weill Cornell Med, Childrens Canc & Blood Fdn Labs, New York, NY 10065 USA

[3] Policlin Univ St Orsola Malpighi, Dept Expt Diagnost & Specialty Med, I-40138 Bologna, BO, Italy

[4] Policlin Univ St Orsola Malpighi, Ctr Appl Biomed Res Lab, I-40138 Bologna, Italy

[5] Univ Bologna, Dept Med & Surg Sci, Bologna, Italy

[6] Univ Bologna, Dept Biol Geol & Environm Sci, I-40138 Bologna, Italy

[7] Queens Univ Belfast, Sch Biol Sci, Belfast BT9 7BL, Antrim, North Ireland

[8] Univ Bologna, Dept Pharm & Biotechnol Alma Mater Studiorum, I-40138 Bologna, Italy

[9] Weill Cornell Med, Feil Family Brain & Mind Res Inst, New York, NY 10065 USA

[10] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA

[11] Weill Cornell Med, Dept Med, New York, NY 10065 USA

[12] Univ Clin Essen, Pediat Clin 3, D-45147 Essen, Germany

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2017年 / 114卷 / 43期

基金：

英国医学研究理事会;

关键词：

exosomes; mitochondrial DNA; cancer stem cells; hormonal therapy; metastasis; EXTRACELLULAR VESICLES; SELF-RENEWAL; GENOMIC DNA; CELLS; MTDNA; MICROENVIRONMENT; CHEMORESISTANCE; METABOLISM; MECHANISM; CAPACITY;

D O I：

10.1073/pnas.1704862114

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：E9066 / E9075

页数：10

共 55 条

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