Modeling glioma intratumoral heterogeneity with primary human neural stem and progenitor cells

Gliomas are notorious for their intratumoral heterogeneity, which drives therapy resistance. Glioma tumor cells mimic a neural stem cell (NSC) hierarchy reminiscent of normal brain development. How intratumoral heterogeneity is shaped by cell-of-origin and various driver mutations is not fully understood. We develop a model of glioma initiation using neural stem and progenitor cells (NSPCs) purified from midgestational human brain tissue, including tripotent NSCs, bipotent glial progenitor cells (GPCs), and unipotent oligodendrocyte progenitor cells (OPCs). We transduced these isogenic lines with defined combinations of oncogenic drivers (TP53, NF1, CDK4, EGFR, and PDGFRA) and transplanted them into mice. We find that OPC-derived tumors harbored a higher proportion of differentiated oligodendrocyte-like cells, reminiscent of low-grade oligodendrogliomas. CDK4 drove a neuron-like subtype, while EGFR drove a GPC-like subtype. Our platform is highly adaptable and allows for modular and systematic interrogation of how cell-of-origin and specific driver mutations shape the tumor landscape.