Glioma-derived miRNA-containing extracellular vesicles induce angiogenesis by reprogramming brain endothelial cells

• Main Authors: Lucero, Rocco, Zappulli, Valentina, Sammarco, Alessandro, Murillo, Oscar D, Cheah, Pike See, Srinivasan, Srimeenakshi, Tai, Eric, Ting, David T., Wei, Zhiyun, Roth, Matthew E., Laurent, Louise C., Krichevsky, Anna M., Breakefield, Xandra O, Milosavljevic, Aleksandar
• Format: Article
• Language: English
• Published: Cell Press 2020
• Online Access: http://psasir.upm.edu.my/id/eprint/89124/1/CANCER.pdf; http://psasir.upm.edu.my/id/eprint/89124/; https://www.cell.com/cell-reports/fulltext/S2211-1247(20)30098-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS221112472030098X%3Fshowall%3Dtrue

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.