title: Extracellular Vesicles from High-Grade Glioma Exchange Diverse Pro-oncogenic Signals That Maintain Intratumoral Heterogeneity.
abstract: A lack of experimental models of tumor heterogeneity limits our knowledge of the complex subpopulation dynamics within the tumor ecosystem. In high-grade gliomas (HGG), distinct hierarchical cell populations arise from different glioma stem-like cell (GSC) subpopulations. Extracellular vesicles (EV) shed by cells may serve as conduits of genetic and signaling communications; however, little is known about how HGG heterogeneity may impact EV content and activity. In this study, we performed a proteomic analysis of EVs isolated from patient-derived GSC of either proneural or mesenchymal subtypes. EV signatures were heterogeneous, but reflected the molecular make-up of the GSC and consistently clustered into the two subtypes. EV-borne protein cargos transferred between proneural and mesenchymal GSC increased protumorigenic behaviors in vitro and in vivo Clinically, analyses of HGG patient data from the The Cancer Genome Atlas database revealed that proneural tumors with mesenchymal EV signatures or mesenchymal tumors with proneural EV signatures were both associated with worse outcomes, suggesting influences by the proportion of tumor cells of varying subtypes in tumors. Collectively, our findings illuminate the heterogeneity among tumor EVs and the complexity of HGG heterogeneity, which these EVs help to maintain. Cancer Res; 76(10); 2876-81. ©2016 AACR.
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Ricklefs
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Marco
authors.initials: M
authors.lastname: Mineo
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Rooj
authors.affiliation: Department of Neurosurgery and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.affiliation: Department of Neurosurgery, Molecular Oncology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Al
authors.initials: A
authors.lastname: Charest
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: Department of Neurology, Neurosurgery and Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Xandra O
authors.initials: XO
authors.lastname: Breakefield
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. abronisz@partners.org jgodlewski@partners.org eachiocca@partners.org.
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. abronisz@partners.org jgodlewski@partners.org eachiocca@partners.org.
authors.forename: Jakub
authors.initials: J
authors.lastname: Godlewski
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. abronisz@partners.org jgodlewski@partners.org eachiocca@partners.org.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bronisz
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis; D049109:Cell Proliferation; D000067128:Extracellular Vesicles / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D040901:Proteomics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays