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Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood–brain barrier

Author

Listed:
  • Naoomi Tominaga

    (National Cancer Center Research Institute
    Graduate School of Medicine, The University of Tokyo
    Research Fellow of the Japan Society for the Promotion of Science (JSPS))

  • Nobuyoshi Kosaka

    (National Cancer Center Research Institute
    University of Oxford, The Tinbergen Building
    The Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellow for Research Abroad)

  • Makiko Ono

    (National Cancer Center Research Institute)

  • Takeshi Katsuda

    (National Cancer Center Research Institute)

  • Yusuke Yoshioka

    (National Cancer Center Research Institute)

  • Kenji Tamura

    (National Cancer Center Research Institute)

  • Jan Lötvall

    (The Sahlgrenska Academy, University of Göteborg)

  • Hitoshi Nakagama

    (Graduate School of Medicine, The University of Tokyo
    National Cancer Center Research Institute)

  • Takahiro Ochiya

    (National Cancer Center Research Institute)

Abstract

Brain metastasis is an important cause of mortality in breast cancer patients. A key event during brain metastasis is the migration of cancer cells through blood–brain barrier (BBB). However, the molecular mechanism behind the passage through this natural barrier remains unclear. Here we show that cancer-derived extracellular vesicles (EVs), mediators of cell–cell communication via delivery of proteins and microRNAs (miRNAs), trigger the breakdown of BBB. Importantly, miR-181c promotes the destruction of BBB through the abnormal localization of actin via the downregulation of its target gene, PDPK1. PDPK1 degradation by miR-181c leads to the downregulation of phosphorylated cofilin and the resultant activated cofilin-induced modulation of actin dynamics. Furthermore, we demonstrate that systemic injection of brain metastatic cancer cell-derived EVs promoted brain metastasis of breast cancer cell lines and are preferentially incorporated into the brain in vivo. Taken together, these results indicate a novel mechanism of brain metastasis mediated by EVs that triggers the destruction of BBB.

Suggested Citation

  • Naoomi Tominaga & Nobuyoshi Kosaka & Makiko Ono & Takeshi Katsuda & Yusuke Yoshioka & Kenji Tamura & Jan Lötvall & Hitoshi Nakagama & Takahiro Ochiya, 2015. "Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood–brain barrier," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7716
    DOI: 10.1038/ncomms7716
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