Glioblastoma-Associated Microglia Reprogramming Is Mediated by Functional Transfer of Extracellular miR-21
Erik R. Abels,
Sybren L.N. Maas,
Lisa Nieland,
Zhiyun Wei,
Pike See Cheah,
Eric Tai,
Christy-Joy Kolsteeg,
Sophie A. Dusoswa,
David T. Ting,
Suzanne Hickman,
Joseph El Khoury,
Anna M. Krichevsky,
Marike L.D. Broekman,
Xandra O. Breakefield
Affiliations
Erik R. Abels
Departments of Neurology and Radiology, Massachusetts General Hospital, and NeuroDiscovery Center, Harvard Medical School, Boston, MA 02129, USA; Corresponding author
Sybren L.N. Maas
Department of Neurosurgery, UMC Utrecht Brain Center, University Medical Center, Utrecht University, 3584 CX Utrecht, the Netherlands
Lisa Nieland
Departments of Neurology and Radiology, Massachusetts General Hospital, and NeuroDiscovery Center, Harvard Medical School, Boston, MA 02129, USA
Zhiyun Wei
Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Pike See Cheah
Departments of Neurology and Radiology, Massachusetts General Hospital, and NeuroDiscovery Center, Harvard Medical School, Boston, MA 02129, USA; Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia
Eric Tai
Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Christy-Joy Kolsteeg
Departments of Neurology and Radiology, Massachusetts General Hospital, and NeuroDiscovery Center, Harvard Medical School, Boston, MA 02129, USA
Sophie A. Dusoswa
Department of Molecular Cell Biology and Immunology, Amsterdam Infection & Immunology Institute and Cancer Center Amsterdam, Amsterdam UMC, 1081 HZ Amsterdam, the Netherlands
David T. Ting
Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Suzanne Hickman
Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
Joseph El Khoury
Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
Anna M. Krichevsky
Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Marike L.D. Broekman
Department of Neurosurgery, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Department of Neurosurgery, Haaglanden Medical Center, 2512 VA The Hague, the Netherlands
Xandra O. Breakefield
Departments of Neurology and Radiology, Massachusetts General Hospital, and NeuroDiscovery Center, Harvard Medical School, Boston, MA 02129, USA; Corresponding author
Summary: Gliomas are primary, diffusely infiltrating brain tumors. Microglia are innate immune cells in the CNS and make up a substantial portion of the tumor mass. Glioma cells shape their microenvironment, communicating with and reprogramming surrounding cells, resulting in enhanced angiogenesis, immune suppression, and remodeling of the extracellular matrix. Glioma cells communicate with microglia, in part by releasing extracellular vesicles (EVs). Mouse glioma cells stably expressing a palmitoylated GFP to label EVs were implanted intracranially into syngeneic miR-21-null mice. Here, we demonstrate functional delivery of miR-21, regulating specific downstream mRNA targets in microglia after uptake of tumor-derived EVs. These findings attest to EV-dependent microRNA delivery as studied in an in vivo-based model and provide insight into the reprograming of microglial cells by tumor cells to create a favorable microenvironment for cancer progression. : Abels et al. show miR-21 transfer from glioma to microglia by palmitoylated GFP-labeled extracellular vesicles in vivo. This transfer results in miR-21 target-specific mRNA downregulation. Following downregulation of Btg2, proliferation in microglia is increased, suggesting reprogramming of microglia in the tumor microenvironment through extracellular vesicles shed by glioma cells.
