Cell Lineage-Based Stratification for Glioblastoma

Glioblastoma, the predominant adult malignant brain tumor, has been computationally classified into molecular subtypes whose functional relevance remains to be comprehensively established. Tumors from genetically engineered glioblastoma mouse models initiated by identical driver mutations in distinct cells of origin portray unique transcriptional profiles reflective of their respective lineage. Here, we identify corresponding transcriptional profiles in human glioblastoma and describe patient-derived xenografts with species-conserved subtype-discriminating functional properties. The oligodendrocyte lineage-associated glioblastoma subtype requires functional ERBB3 and harbors unique therapeutic sensitivities. These results highlight the importance of cell lineage in glioblastoma independent of driver mutations and provide a methodology for functional glioblastoma classification for future clinical investigations. [Display omitted] •Tumor suppressor loss in NSCs and OLCs generate distinct murine GBM subtypes•Human GBM subtypes identified based on species-conserved transcriptional profiles•Mouse and human cell lineage subtypes exhibit distinct tumor properties•OLC-associated GBMs show ERBB3 dependence and unique therapeutic sensitivity Wang et al. identify lineage-specific subtypes in mouse and human glioblastoma that harbor distinct functional properties and therapeutic vulnerabilities, highlighting the role of cell lineage in glioblastoma and providing a classification system for future clinical investigations.