Glioblastoma is spatially organized by neurodevelopmental programs and a glial-like wound healing response

Abstract

Glioblastoma is the deadliest brain cancer, characterized by great cellular diversity and unique histology. To understand the spatial organization of transcriptional cell states, we mapped the expression of 888 genes in centimeter-scaletissuesectionsfromalargepatientcohort.Wefoundahierarchyofcellularstatesakintonormal brain development, including proliferating and differentiated cells interacting with the stroma. We discovered that mesenchymal-like glioblastoma cells comprised a major glial-like wound-response component and a distinct gliosarcoma-specific malignant fibroblast type. Our analysis highlighted hypoxia, tissue damage, and woundhealingasmajorfactorsinglioblastomaspatialorganization.Tumormicroenvironment variedalongthe hypoxia gradient, inducing the recruitment of monocytes and pro-tumorigenic macrophages, and propagating wound response program activation in malignant glial cells. Our study reveals the dynamic progression of glioblastoma organization independent of its mutational profile, in response to tumor-induced injury.