Glioblastoma (GBM) recurrence originates from invasive margin cells that escape surgical debulking, but to what extent these cells resemble their bulk counterparts remains unclear. Here, we generated three immunocompetent somatic GBM mouse models, driven by subtype-associated mutations, to compare matched bulk and margin cells. We find that, regardless of mutations, tumors converge on common sets of neural-like cellular states. However, bulk and margin have distinct biology. Injury-like programs associated with immune infiltration dominate in the bulk, leading to the generation of lowly proliferative injured neural progenitor-like cells (iNPCs). iNPCs account for a significant proportion of dormant GBM cells and are induced by interferon signaling within T cell niches. In contrast, developmental-like trajectories are favored within the immune-cold margin microenvironment resulting in differentiation toward invasive astrocyte-like cells. These findings suggest that the regional tumor microenvironment dominantly controls GBM cell fate and biological vulnerabilities identified in the bulk may not extend to the margin residuum.
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

h4>Summary/h4> Glioblastoma recurrence originates from invasive cells at the tumour margin that escape surgical debulking, but their biology remains poorly understood. Here we generated three somatic mouse models recapitulating the main glioblastoma driver mutations to characterise margin cells. We find that, regardless of genetics, tumours converge on a common set of neural- like cellular states. However, bulk and margin display distinct neurogenic patterns and immune microenvironments. The margin is immune-cold and preferentially follows developmental-like trajectories to produce astrocyte-like cells. In contrast, injury-like programmes dominate in the bulk, are associated with immune infiltration and generate lowly-proliferative injured neural progenitor-like (iNPCs) cells. In vivo label-retention approaches further demonstrate that iNPCs account for a significant proportion of dormant glioblastoma cells and are induced by interferon signalling within T-cell niches. These findings indicate that tumour region is a major determinant of glioblastoma cell fate and therapeutic vulnerabilities identified in bulk may not extend to the margin residuum.