The following is a summary of “Single-nucleus RNA-sequencing Reveals a MET+ Oligodendrocyte Subpopulation that Promotes Proliferation of Radiation-Induced Gliomas,” published in the September 2024 issue of Oncology by Huang et al.

Radiation-induced gliomas (RIGs) are severe late complications of radiotherapy with a dismal median survival rate of 6 to 11 months. These tumors exhibit a unique molecular profile and may originate from a glial lineage distinct from primary malignancies or diffuse midline gliomas (DMGs). This study sought to investigate the intratumoral heterogeneity within RIGs to elucidate their cellular origins and characteristics, thereby enhancing the understanding of this rare tumor type. To analyze intratumoral diversity and cellular interactions, researchers utilized single-nucleus RNA sequencing on formalin-fixed, paraffin-embedded samples from two RIGs and two DMGs. The comprehensive analysis included gene set enrichment, pseudotime trajectory, and cell communication studies supplemented by immunofluorescence staining, proliferation assays, and RNA-seq validation. The findings uncovered distinct heterogeneity in oligodendrocytes between DMG and RIG samples. 

Notably, a unique subpopulation of oligodendrocytes in RIGs, characterized by the mesenchymal-epithelial transition factor (c-MET) expression, was identified as MET+ oligodendrocytes (MET+ ODs). These MET+ ODs displayed cancer cell-like traits, including heightened mitotic activity, cancer-associated gene expression, and extensive copy number variations. Cell communication analyses revealed that MET+ ODs engage actively with G1/S and G2/M cycling cells via the neural cell adhesion molecule (NCAM) signaling pathway, potentially fostering the proliferation of malignant cycling cells. Further integration with existing RNA-seq data reinforced these findings. Immunostaining confirmed the presence of MET+ ODs in RIGs, and in vitro studies demonstrated that NCAM pathway activation significantly enhanced RIG tumor cell proliferation. Additionally, radiation exposure in vitro induced a transformation of oligodendrocytes toward a phenotype resembling MET+ ODs. 

These results indicate that RIGs possess a distinct oligodendrocyte composition compared to DMGs, with MET+ ODs potentially playing a pivotal role in tumorigenesis and malignant cell proliferation. Targeting MET+ ODs could provide new avenues for clinical surveillance and therapeutic interventions.

Source: sciencedirect.com/science/article/pii/S0360301624033303