Affiliations 

  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
  • 2 Department of Comparative Biomedicine and Food Science, University of Padua, Padua, Italy; Departments of Neurology and Radiology, Massachusetts General Hospital, Boston, MA 02114, USA; Neuroscience Program, Harvard Medical School, Boston, MA 02115, USA. Electronic address: valentina.zappulli@unipd.it
  • 3 Department of Comparative Biomedicine and Food Science, University of Padua, Padua, Italy; Departments of Neurology and Radiology, Massachusetts General Hospital, Boston, MA 02114, USA; Neuroscience Program, Harvard Medical School, Boston, MA 02115, USA
  • 4 Departments of Neurology and Radiology, Massachusetts General Hospital, Boston, MA 02114, USA; Neuroscience Program, Harvard Medical School, Boston, MA 02115, USA; Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Seri Kembangan, Selangor, Malaysia
  • 5 Department of Obstetrics, Gynecology, and Reproductive Sciences and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA
  • 6 Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
  • 7 Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
  • 8 Departments of Neurology and Radiology, Massachusetts General Hospital, Boston, MA 02114, USA; Neuroscience Program, Harvard Medical School, Boston, MA 02115, USA
  • 9 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: amilosav@bcm.edu
Cell Rep, 2020 02 18;30(7):2065-2074.e4.
PMID: 32075753 DOI: 10.1016/j.celrep.2020.01.073

Abstract

Glioblastoma (GBM) is characterized by aberrant vascularization and a complex tumor microenvironment. The failure of anti-angiogenic therapies suggests pathways of GBM neovascularization, possibly attributable to glioblastoma stem cells (GSCs) and their interplay with the tumor microenvironment. It has been established that GSC-derived extracellular vesicles (GSC-EVs) and their cargoes are proangiogenic in vitro. To further elucidate EV-mediated mechanisms of neovascularization in vitro, we perform RNA-seq and DNA methylation profiling of human brain endothelial cells exposed to GSC-EVs. To correlate these results to tumors in vivo, we perform histoepigenetic analysis of GBM molecular profiles in the TCGA collection. Remarkably, GSC-EVs and normal vascular growth factors stimulate highly distinct gene regulatory responses that converge on angiogenesis. The response to GSC-EVs shows a footprint of post-transcriptional gene silencing by EV-derived miRNAs. Our results provide insights into targetable angiogenesis pathways in GBM and miRNA candidates for liquid biopsy biomarkers.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.