Cell Lineage-Based Glioblastoma Stratification in Mice Reveals Functional Alignment with Patient Derived Models

Abstract

Glioblastoma, the predominant adult malignant brain tumor, is subject to a limited number of driver mutations and has been computationally classified into subtypes whose functional relevance remains to be established. We have previously reported genetically engineered glioblastoma mouse models initiated by identical driver mutations in two distinct cells of origin: adult subventricular zone neural stem cells and oligodendrocyte lineage progenitors. These biologically and functionally separable tumors portray unique transcriptional profiles reflective of their respective lineage. Here, we identify corresponding transcriptional profiles among human glioblastoma data sets and describe patient derived xenografts with parallel features including species-conserved subtype-discriminating functional properties. Both mouse and human oligodendrocyte lineage associated glioblastoma subtypes exhibit functional ErbB3 receptor requirement and unique shared therapeutic sensitivities. We thus provide a biological lineage-based classification for glioblastoma. Significance: Glioblastoma has no effective treatment. Elucidation of biological and functional stratification may, as demonstrated here, reveal therapeutic sensibilities that are masked in the absence of subtype stratification.