An aberrant INSM1-dependent intermediate neuronal progenitor state drives tumorigenesis in a human stem cell model of glioblastoma

ABSTRACT: Glioblastoma (GBM) is an aggressive, incurable brain tumor driven by heterogeneity between tumor cell-intrinsic and -extrinsic states for rapid evolution. To investigate how canonical GBM mutations promote functional plasticity, we developed an isogenic human neural stem cell (NSC) model of GBM by sequential addition of TERT promoter, TP53, and PDGFRA point mutations. TP53 loss-of-function increased TERT expression during serial mutagenesis, but only triple mutant NSCs reliably formed lethal in vivo tumors that recapitulate GBM. Tumor cell evolution began with stress-related metabolic changes and transitioned toward neuronal progenitor networks driven by transcription factor INSM1, which is highly expressed in human GBM tumors and intermediate progenitor cells during development that give rise to neuronal progenitors. Remarkably, inhibiting INSM1 in triple mutant NSCs caused reversal of oncogenic gene expression and functions to those of non-tumorigenic wildtype NSCs. These findings highlight the functional importance of an aberrant intermediate neuronal progenitor state in GBM pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229901 | GEO | 2025/04/13

REPOSITORIES: GEO