title: Extracellular vesicles modulate the glioblastoma microenvironment via a tumor suppression signaling network directed by miR-1.
abstract: Extracellular vesicles have emerged as important mediators of intercellular communication in cancer, including by conveying tumor-promoting microRNAs between cells, but their regulation is poorly understood. In this study, we report the findings of a comparative microRNA profiling and functional analysis in human glioblastoma that identifies miR-1 as an orchestrator of extracellular vesicle function and glioblastoma growth and invasion. Ectopic expression of miR-1 in glioblastoma cells blocked in vivo growth, neovascularization, and invasiveness. These effects were associated with a role for miR-1 in intercellular communication in the microenvironment mediated by extracellular vesicles released by cancer stem-like glioblastoma cells. An extracellular vesicle-dependent phenotype defined by glioblastoma invasion, neurosphere growth, and endothelial tube formation was mitigated by loading miR-1 into glioblastoma-derived extracellular vesicles. Protein cargo in extracellular vesicles was characterized to learn how miR-1 directed extracellular vesicle function. The mRNA encoding Annexin A2 (ANXA2), one of the most abundant proteins in glioblastoma-derived extracellular vesicles, was found to be a direct target of miR-1 control. In addition, extracellular vesicle-derived miR-1 along with other ANXA2 extracellular vesicle networking partners targeted multiple pro-oncogenic signals in cells within the glioblastoma microenvironment. Together, our results showed how extracellular vesicle signaling promotes the malignant character of glioblastoma and how ectopic expression of miR-1 can mitigate this character, with possible implications for how to develop a unique miRNA-based therapy for glioblastoma management.
authors: Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Department of Molecular and Cellular Biochemistry, the Ohio State University Medical Center, Columbus, OH 43210, USA.
authors: Agnieszka
authors: A
authors: Bronisz
authors: Department of Neurological Surgery, the Ohio State University Medical Center, Columbus, OH 43210, USA.
authors: Yan
authors: Y
authors: Wang
authors: Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Department of Neurological Surgery, the Ohio State University Medical Center, Columbus, OH 43210, USA.
authors: Michal O
authors: MO
authors: Nowicki
authors: Department of Neurological Surgery, the Ohio State University Medical Center, Columbus, OH 43210, USA.
authors: Pierpaolo
authors: P
authors: Peruzzi
authors: Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Khairul
authors: K
authors: Ansari
authors: Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Department of Neurological Surgery, the Ohio State University Medical Center, Columbus, OH 43210, USA.
authors: Daisuke
authors: D
authors: Ogawa
authors: Neuroscience Center at Massachusetts General Hospital, Charlestown, MA 02129.
authors: Leonora
authors: L
authors: Balaj
authors: Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Gianluca
authors: G
authors: De Rienzo
authors: Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Marco
authors: M
authors: Mineo
authors: Department of Neurological Surgery, the Ohio State University Medical Center, Columbus, OH 43210, USA.
authors: Ichiro
authors: I
authors: Nakano
authors: Department of Molecular and Cellular Biochemistry, the Ohio State University Medical Center, Columbus, OH 43210, USA.
authors: Michael C
authors: MC
authors: Ostrowski
authors: Neuroscience Center at Massachusetts General Hospital, Charlestown, MA 02129.
authors: Fred
authors: F
authors: Hochberg
authors: Neuroscience Center at Massachusetts General Hospital, Charlestown, MA 02129.
authors: Ralph
authors: R
authors: Weissleder
authors: Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Department of Neurological Surgery, the Ohio State University Medical Center, Columbus, OH 43210, USA.
authors: Sean E
authors: SE
authors: Lawler
authors: Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Department of Neurological Surgery, the Ohio State University Medical Center, Columbus, OH 43210, USA.
authors: E Antonio
authors: EA
authors: Chiocca
authors: Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Department of Neurological Surgery, the Ohio State University Medical Center, Columbus, OH 43210, USA.
authors: Jakub
authors: J
authors: Godlewski
mesh_terms: D000818:Animals; D001692:Biological Transport; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: C544547:MIRN1 microRNA, human; D035683:MicroRNAs