Precancerous Cells Initiate Glioblastoma Evolution and Contribute to Intratumoral Heterogeneity

Abstract Neural stem cells (NSCs) in the subventricular zone (SVZ) are identified as cells-of-origin harboring driver mutations in glioblastoma (GBM), which is the most devastating brain tumor with highly heterogeneous nature. However, the sequential transformation of a limited number of mutation-harboring NSCs into a distant tumor with high intratumoral heterogeneity remains poorly understood. In this study, we have identified transcriptionally distinct types of mutation-harboring precancerous cells in our spontaneous, somatic mouse model recapitulating human GBM evolution as well as in tumor-free SVZ tissues from patients. These precancerous cells emerge via oligodendrocyte lineage specification, exhibiting unique transcriptional programs involving dysregulated translations and extracellular matrix remodeling. Subsequently, they give rise to heterogeneous tumor cell populations by activating multiple programs crucial for gliomagenesis. Our findings highlight the pivotal role of precancerous cells in tumor evolution and intratumoral heterogeneity, suggesting their potential as a novel therapeutic target for GBM.