Journal
BRAIN
Volume 144, Issue 2, Pages 636-654Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awaa408
Keywords
glioblastoma; myelin-associated infiltration; radiogenomics; nogo receptor
Categories
Funding
- National Cancer Center, Korea [NCC-1810121, NCC-1810861, NCC-1810863]
- National Research Foundation of Korea (NRF) - Ministry of Science and ICT [NRF-2016R1A2B4007413, NRF-2017R1A2B4011741, NRF-2017R1D1A1B03033303, 2019R1F1A1062650]
- Basic Research Lab Program through the National Research Foundation of Korea (NRF) [NRF-2018R1A4A1025860]
- National Research Foundation of Korea [2019R1F1A1062650] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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The study identified NgR1 as a key player in suppressing myelin-associated infiltration in glioblastoma cells through deubiquitinating activity of USP1. Pimozide upregulates NgR1 by post-translational targeting of USP1, sensitizing glioma stem cells to myelin inhibition. Downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival in primary human glioblastoma.
As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients.
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