Glioblastoma-Derived Extracellular Vesicles Facilitate Transformation of Astrocytes via Reprogramming Oncogenic Metabolism

Ailiang Zeng; Zhiyun Wei; Rosalia Rabinovsky; Hyun Jung Jun; Rachid El Fatimy; Evgeny Deforzh; Ramil Arora; Yizheng Yao; Shun Yao; Wei Yan; Erik J Uhlmann; Alain Charest; Yongping You; Anna M Krichevsky

doi:10.1016/j.isci.2020.101420

Glioblastoma-Derived Extracellular Vesicles Facilitate Transformation of Astrocytes via Reprogramming Oncogenic Metabolism

iScience. 2020 Aug 21;23(8):101420. doi: 10.1016/j.isci.2020.101420. Epub 2020 Jul 29.

Authors

Affiliations

¹ Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
² Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China. Electronic address: zwei@bwh.harvard.edu.
³ Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁴ Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
⁵ Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁶ Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Center for Pituitary Tumor Surgery, Department of Neurosurgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510062, China.
⁷ Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
⁸ Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁹ Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: akrichevsky@bwh.harvard.edu.

Abstract

Glioblastoma (GBM) may arise from astrocytes through a multistep process involving a progressive accumulation of mutations. We explored whether GBM-derived extracellular vesicles (EVs) may facilitate neoplastic transformation and malignant growth of astrocytes. We utilized conditioned media (CM) of cultured glioma cells, its sequential filtration, diverse cell-based assays, RNA sequencing, and metabolic assays to compare the effects of EV-containing and EV-depleted CM. GBM EVs facilitated the neoplastic growth of pre-transformed astrocytes but not normal human or mouse astrocytes. They induced proliferation, self-renewal, and colony formation of pre-transformed astrocytes and enhanced astrocytoma growth in a mouse allograft model. GBM EVs appear to reprogram astrocyte metabolism by inducing a shift in gene expression that may be partly associated with EV-mediated transfer of full-length mRNAs encoding ribosomal proteins, oxidative phosphorylation, and glycolytic factors. Our study suggests an EV/extracellular RNA (exRNA)-mediated mechanism that contributes to astrocyte transformation via metabolic reprograming and implicates horizontal mRNA transfer.

Keywords: Biological Sciences; Cancer; Cell Biology.

Abstract

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