Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Valentina Zappulli
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; Corresponding author
Alessandro Sammarco
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
Oscar D. Murillo
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Pike See Cheah
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
Srimeenakshi Srinivasan
Department of Obstetrics, Gynecology, and Reproductive Sciences and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA
Eric Tai
Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
David T. Ting
Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Zhiyun Wei
Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Matthew E. Roth
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Louise C. Laurent
Department of Obstetrics, Gynecology, and Reproductive Sciences and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA
Anna M. Krichevsky
Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Xandra O. Breakefield
Departments of Neurology and Radiology, Massachusetts General Hospital, Boston, MA 02114, USA; Neuroscience Program, Harvard Medical School, Boston, MA 02115, USA
Aleksandar Milosavljevic
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Corresponding author
Summary: 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. : Extensive intercellular interactions occur within the notoriously heterogeneous tumor microenvironment of GBM. Lucero et al. identify distinct angiogenic gene regulatory responses of brain endothelial cells to growth factors and to extracellular vesicles (EVs) secreted by GBM stem-like cells. The response to EVs shows a footprint of EV-derived miRNAs. Keywords: angiogenesis, biomarker, cancer stem cell, deconvolution, glioblastoma, exRNA, extracellular vesicle, miRNA, reprogramming, tumor microenvironment
