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
Affiliations
Ailiang Zeng
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
Zhiyun Wei
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; Corresponding author
Rosalia Rabinovsky
Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Hyun Jung Jun
Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
Rachid El Fatimy
Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Evgeny Deforzh
Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Ramil Arora
Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Yizheng Yao
Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Shun Yao
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
Wei Yan
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
Erik J. Uhlmann
Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Alain Charest
Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Yongping You
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
Anna M. Krichevsky
Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Corresponding author
Summary: 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.
