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.