Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021;
Children's Cancer and Blood Foundation Laboratories, Weill Cornell Medicine, New York, NY 10065.
Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):E9066-E9075. doi: 10.1073/pnas.1704862114. Epub 2017 Oct 11.
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.
线粒体 DNA 的水平转移及其在介导治疗耐药和休眠退出中的作用从未被研究过。在这里，我们在接受激素治疗耐药（HTR）转移性乳腺癌患者的循环细胞外囊泡（EV）中鉴定出完整的线粒体基因组。我们生成了 HTR 转移性疾病的异种移植模型，其特征是外周循环中的 EV 含有 mtDNA。此外，这些人 HTR 细胞获得了宿主衍生的（鼠）mtDNA，促进了雌激素受体非依赖性氧化磷酸化（OXPHOS）。功能研究鉴定出源自癌症相关成纤维细胞（CAF）的 EV（来自患者和异种移植模型），其负载有完整基因组 mtDNA，是这种表型的介导物。具体而言，用 CAF 衍生的 mtDNA EV 处理激素治疗（HT）初治细胞或代谢休眠的 HT 治疗细胞群，可在体外和体内促进代谢静止和 HTR 疾病的逃逸。此外，这种表型与 EV mtDNA 的获得有关，尤其是在癌症干细胞样细胞中，EV mtRNA 的表达和 OXPHOS 的恢复。总之，我们已经证明，来自 EV 的 mtDNA 的水平转移作为一种致癌信号，促进了治疗诱导的癌症干细胞样细胞休眠的退出，并导致了依赖 OXPHOS 的乳腺癌的内分泌治疗耐药。
