The malignant transformation roadmap of human neural stem cells toward high grade glioma

We established novel, highly-penetrant in vivo high grade glioma (HGG) models from gene-edited human neural stem cells (hNSCs) harboring glioblastoma-relevant tumor suppressor mutations. Time-series analyses combining histology, deep whole exome sequencing, bulk RNA-seq and single-cell RNA-seq allowed us to depict a comprehensive landscape of how mutant hNSCs give rise to each cellular compartment of HGGs in vivo, and define a critical time window when tumorigenesis diverge from normal differentiation. Strikingly, we identified a minor but persistent NSC-like population across different stages of in vivo tumorigenesis, which exhibited stage-specific upregulation of NPC-like, AC-like and OPC-like programs, sequentially generating neuron, astrocyte and oligodendrocyte lineages, respectively. Reconstruction of a gliomagenesis tree highlights this hNSC-to-GSC-like trajectory, identifies novel regulators of gliomagenesis, and provides a blueprint for stage-specific interventions against this stem-like cell population. please note that M0, 1M and 2M correspond to T0, T1 and T2 in text, respectively.