title: Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier.
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.
authors.affiliation: 1] Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan [2] Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyou-ku, Tokyo 113-0033, Japan [3] Research Fellow of the Japan Society for the Promotion of Science (JSPS), Chiyoda-Ku, Tokyo 102-0083, Japan.
authors.forename: Naoomi
authors.initials: N
authors.lastname: Tominaga
authors.affiliation: 1] Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan [2] Department of Zoology, University of Oxford, The Tinbergen Building, South Parks Road, Oxford OX1 3PS, United Kingdom [3] The Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellow for Research Abroad, Chiyoda-Ku, Tokyo 102-0083, Japan.
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Kosaka
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Ono
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Katsuda
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Division of Breast and Medical Oncology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Department of Internal Medicine and Department of Respiratory Medicine and Allergology, The Sahlgrenska Academy, University of Göteborg, Box 424, SE-405 30 Gothenburg, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Lötvall
authors.affiliation: 1] Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyou-ku, Tokyo 113-0033, Japan [2] Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D000067128:Extracellular Vesicles / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D021381:Protein Transport
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human
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