INSM1 governs a neuronal progenitor state that drives glioblastoma in a human stem cell model

Glioblastoma (GBM) is an aggressivea lethal brain tumorcancer marked by functional plasticity driven by the interplay between tumor cell-intrinsic mutations and -extrinsic heterogeneity, enabling rapid evolutiontheir interplay with developmental programs. To investigate how canonical GBM glioblastoma mutations promote functional plasticity, we have developeded an isogenic human neural stem cell (NSC) model of glioblastoma GBM by sequential addition of TERT promoter, TP53, and PDGFRA point mutations. TP53 loss-of-function increasesd TERT TERT expression during serial mutagenesis, but only triple mutant NSCs reliably formed lethal brain tumors in vivo that recapitulate glioblastomaGBM. Tumor cell evolution triggersed stress-related metabolic changes and transitionsed toward a neuronal progenitor network driven by transcription factor INSM1. INSM1 is highly expressed in human glioblastoma GBM tumors and, during cortical development, in intermediate progenitor cells (IPC), which give rise to neurons. Remarkably, INSM1 knockdown in triple mutant NSCs and primary glioblastoma GBM cells disrupted disrupts oncogenic gene expression and function and inhibited inhibits the in vivo tumorigenicity of triple mutant NSCs, highlighting the functional importance of an intermediate progenitor cellIPC-like cell state in glioblastoma GBM pathogenesis.