The primitive oligodendrocyte precursor cell (OPC) lineage is a primary contributor to gliomagenesis.

  • Major finding: The primitive oligodendrocyte precursor cell (OPC) lineage is a primary contributor to gliomagenesis.

  • Mechanism: Reprogramming OPC intermediates to a stem-like state increases cell cycling and drives tumor growth.

  • Impact: Targeting factors that specify glial fate may serve as a potential therapy in patients with glioma.

Previous attempts to uncover the molecular connections between normal glial progenitors and tumor cells have yielded limited success, largely due to high tumor heterogeneity. Weng, Wang, Wang, and colleagues exploited single-cell RNA sequencing (scRNA-seq) from neonatal mouse cortices and a murine model of glioblastoma to demonstrate that oligodendrocyte precursor cells (OPC) are a major contributor to glioma formation. Gene ontology analysis of neonatal astrocyte lineage cells identified nine clusters with distinct gene expression signatures and corresponding subpopulations, including astrocytes and OPCs. Within the OPC cluster were two distinct subclusters, OPCs and a primitive OPC subpopulation (pri-OPC). scRNA-seq of the OPC population of the neonatal cortex revealed eight distinct groups of cells, the most abundant of which were OPCs, pri-OPCs, and cycling OPCs. In a murine model of glioma, pri-OPC–like cells were the most abundant population in malignant tissue. Within tumor tissue, pri-OPC–like cells expressed high levels of cell stemness and stress-associated and hypoxia-associated gene signatures, harbored increased chromosomal aberrations, and exhibited higher rates of cell-cycle progression as tumors developed, suggesting that genomic instability in pri-OCP–like cells leads to acquisition of stem cell–like properties that subsequently fuel tumor growth. Analysis of differentially expressed genes identified the transcription factor gene Zfp36l1 as the primary driver of the OPC lineage commitment and glioma growth. In neonatal cortices and during glioma development, deletion of Zfp36l1 resulted in reduced OPC and pri-OPC populations, reduced glioma cell proliferation and tumor burden, and extended overall survival. In human glioma, expression of ZFP36L1 was enhanced compared to normal brain, and depletion of ZFP36L1 in vitro reduced spheroid formation and impaired cell-cycle progression. Taken together, these results identify pri-OPCs as the predominant contributors to gliomagenesis and show that disruption of lineage commitment to this cell type may serve as an effective therapy against glioma.

Weng Q, Wang J, Wang J, He D, Cheng Z, Zhang F, et al. Single-cell transcriptomics uncovers glial progenitor diversity and cell fate determinants during development and gliomagenesis. Cell Stem Cell 2019;24:707–23.

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