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

## TL;DR

The study identifies INSM1 as a key driver of a neural progenitor state that promotes glioblastoma in a human stem cell model.

## Contribution

The novel contribution is the discovery that INSM1 governs a neuronal progenitor state critical for glioblastoma development.

## Key findings

- Triple mutant NSCs reliably form lethal brain tumors resembling glioblastoma.
- INSM1 is highly expressed in glioblastoma tumors and in intermediate progenitor cells during cortical development.
- INSM1 knockdown disrupts oncogenic gene expression and inhibits tumor formation.

## Abstract

Glioblastoma is a lethal brain cancer marked by functional plasticity driven by tumor cell-intrinsic mutations and their interplay with developmental programs. To investigate how canonical glioblastoma mutations promote functional plasticity, we have developed an isogenic human neural stem cell (NSC) model of glioblastoma by sequential addition of TERT promoter, TP53, and PDGFRA point mutations. TP53 loss-of-function increases TERT expression during serial mutagenesis, but only triple mutant NSCs reliably form lethal brain tumors in vivo that recapitulate glioblastoma. Tumor cell evolution triggers stress-related metabolic changes and transitions toward a neuronal progenitor network driven by transcription factor INSM1. INSM1 is highly expressed in human glioblastoma tumors and, during cortical development, in intermediate progenitor cells, which give rise to neurons. Remarkably, INSM1 knockdown in triple mutant NSCs and primary glioblastoma cells disrupts oncogenic gene expression and function and inhibits the in vivo tumorigenicity of triple mutant NSCs, highlighting the functional importance of an intermediate progenitor cell-like cell state in glioblastoma pathogenesis.

Glioblastoma (GBM) is characterized by a high degree of heterogeneity and plasticity due to interplay with neural developmental programs. Here, the authors develop a model of GBM by introducing sequential oncogenic mutations in human neural stem cells and using this, identify INSM1 as a driver of a neural progenitor gene network promoting tumorigenesis.