Neurodevelopmental hijacking of oligodendrocyte lineage programs drives glioblastoma infiltration

Glioblastoma (GBM) is an aggressive brain tumor with a highly invasive nature. Despite the clinical relevance of this behavior, the molecular underpinnings of infiltrating GBM cells in the peritumoral zone remain underexplored in patients. Here, we show that peritumoral progenitor-like GBM cells activate transcriptional programs associated with increased invasivity, synaptic activity, and NOTCH signaling. These cells spatially colocalize with neurons and exhibit an increased propensity for neuronal crosstalk. The epigenetic encoding of these infiltrative cells mirrors that of uncommitted oligodendrocyte progenitor cells (OPCs) in the developing human brain, a neurodevelopmental state marked by increased synaptic and migratory potential. Functional perturbation of a nominated regulatory factor, ZEB1, confirmed its role in maintaining the invasive and uncommitted developmental potential of infiltrative GBM cells. Our findings provide insights into the neurodevelopmental hijacking that drives GBM infiltration in patients, rationalizing further investigation into targeting differentiation potential as a therapeutic strategy. • Progenitor-like GBM cells with synaptic activity infiltrate peritumoral regions • Neuron-tumor crosstalk promotes invasiveness of infiltrating GBM cells • Infiltrating cells hijack OPC lineage TFs to maintain an uncommitted state • Disrupting OPC lineage TFs drives a less invasive, differentiated malignant phenotype Wu et al. demonstrate that glioblastoma (GBM) infiltration is driven by progenitor-like tumor cells that mimic uncommitted oligodendrocyte progenitors, exhibiting enhanced invasivity, neuron-tumor interactions, and synaptic activity. This study elucidates how GBM hijacks developmental mechanisms for invasion, highlighting differentiation cell state plasticity as a potential therapeutic strategy.