Glioblastoma cell fate is differentially regulated by the microenvironments of the tumour bulk and infiltrative margin.

Glioblastoma recurrence originates from invasive cells that escape surgical resection, but their biology remains poorly understood. Here we generated three somatic mouse models recapitulating the main driver mutations of the human disease to characterise the infiltrative tumour margin. We find that, regardless of genetics, tumours are fuelled by highly proliferative glioma stem-like cells (GSCs) resembling active neural stem cells (NSCs), which recapitulate normal and injury-induced neurogenesis in both bulk and margin. Surprisingly, GSCs are evenly distributed across both regions, suggesting that invasive potential is uncoupled from stemness. However, tumour region influences fate choice, with margin cells progressing towards astrocyte-like, and bulk cells towards injured NSC-like (iNSCs) fates. iNSCs account for a significant proportion of dormant glioblastoma cells and are induced by interferon signalling within T-cell-rich niches that form selectively in the bulk. These findings identify key differences between bulk and margin and indicate that glioblastoma cell fate is under cell-extrinsic control. Overall design: Full-length single cell RNA sequencing libraries were prepared using the Smart-seq2 protocol with minor modifications.