A neurovascular progenitor sits at the nexus of glioblastoma lineage trajectories

Abstract

Glioblastoma (GBM) exhibits developmental programs and marked cellular heterogeneity, yet how these features are organized into connected lineage hierarchies remains unclear. Here we identify a rare tumor-intrinsic population, termed the neurovascular progenitor (NVP), that occupies an intermediate position between the major GBM organizational axes. NVP cells co-express neural progenitor and perivascular transcriptional features, are consistently detected across independent patient cohorts, retain canonical GBM copy-number alterations, and localize in situ in both vessel-associated and parenchymal niches. Using direct-from-patient lineage tracing in a human organoid tumor transplantation system, we show that individual NVP cells clonally generate both neural-like and mesenchymal/vascular-like malignant progeny, providing a concrete lineage link between states that are commonly considered mutually exclusive. Despite comprising [~]1% of tumor cells, NVP-derived lineages account for a majority of observed tumor cell types and disproportionately contribute to cycling compartments. Orthogonally, ablation of NVP-associated programs in an in vivo GBM model remodels tumor composition, elicits compensatory progenitor states, and significantly prolongs survival. Together, these findings position NVP as a fate-restricted yet highly influential lineage intermediate that serves as a functional bridge and organizational nexus within GBM hierarchies, linking population-level lineage architecture to the behavior of a specific progenitor cell type.