Precancerous OPC-Like Cells Drive Glioblastoma Evolution And Shape Intratumoral Heterogeneity

초록

Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by profound intratumoral heterogeneity. Recent studies have identified neural stem cells (NSCs) in the subventricular zone (SVZ) as potential cells-of-origin harboring early driver mutations. However, the stepwise transformation of these rare, mutation-bearing NSCs into heterogeneous tumor populations remains poorly understood. In this study, using a spontaneous somatic mouse model that recapitulates human gliomagenesis, as well as tumor-free SVZ tissues from GBM patients, we identified transcriptionally distinct precancerous cells harboring oncogenic mutations. These cells emerge through oligodendrocyte progenitor-like lineage specification and exhibit aberrant transcriptional programs, including dysregulated translation and extracellular matrix remodeling. Single-cell transcriptomic analysis revealed transitional cell states and progressive acquisition of gliomagenic programs, leading to the emergence of molecularly diverse malignant cell populations. Our findings demonstrate that these OPC-like precancerous cells serve as a critical intermediate in GBM evolution and a driver of intratumoral molecular heterogeneity. This work provides a single-cell atlas of early gliomagenesis and identifies a potential window for therapeutic intervention targeting precancerous cell states.