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Glioblastoma (GBM) is an incurable disease with high intratumoral heterogeneity. Bioinformatic studies have examined transcriptional heterogeneity with differing conclusions. Here, we characterize GBM heterogeneity and highlight critical phenotypic and hierarchical roles for quiescent cancer stem cells (qCSCs). Unsupervised single-cell transcriptomic analysis of patient-derived xenografts (PDXs) delineates six GBM transcriptional states with unique tumor exclusive gene signatures, five of which display congruence with central nervous system (CNS) cell lineages. We employ a surrogate tumor evolution assay by serial xenograft transplantation to demonstrate faithful preservation of somatic mutations, transcriptome, and qCSCs. PDX chemotherapy results in CSC resistance and expansion, also seen in recurrent patient GBM. In aggregate, these novel GBM transcriptional signatures exclusively identify tumor cells and define the hierarchical landscape as stable biologically discernible cell types that allow capture of their evolution upon recurrence, emphasizing the importance of CSCs and demonstrating general relevance to all GBM. [Display omitted] • GBM heterogeneity delineated with six signature-defined transcriptional states • Demonstration of an essential role for quiescent cancer stem cells in GBM • Faithful preservation of quiescent cancer stem cells in serial PDX transplantation • Enrichment of quiescent cancer stem cells upon chemotherapy or tumor recurrence GBM heterogeneity explains therapy failure. Xie et al. characterize the essential role of quiescent cancer stem cells in therapy resistance and tumor recurrence. This study highlights the importance of integrating quiescent cancer stem cells in the design and evaluation of therapeutics for GBM patients. [ABSTRACT FROM AUTHOR]

We test the hypothesis that glioblastoma harbors quiescent cancer stem cells that evade anti-proliferative therapies. Functional characterization of spontaneous glioblastomas from genetically engineered mice reveals essential quiescent stem-like cells that can be directly isolated from tumors. A derived quiescent cancer-stem-cell-specific gene expression signature is enriched in pre-formed patient GBM xenograft single-cell clusters that lack proliferative gene expression. A refined human 118-gene signature is preserved in quiescent single-cell populations from primary and recurrent human glioblastomas. The F3 cell-surface receptor mRNA, expressed in the conserved signature, identifies quiescent tumor cells by antibody immunohistochemistry. F3-antibody-sorted glioblastoma cells exhibit stem cell gene expression, enhance self-renewal in culture, drive tumor initiation and serial transplantation, and reconstitute tumor heterogeneity. Upon chemotherapy, the spared cancer stem cell pool becomes activated and accelerates transition to proliferation. These results help explain conventional treatment failure and lay a conceptual framework for alternative therapies. [Display omitted] • Isolation and functional characterization of quiescent glioblastoma cancer stem cells • A 728 murine GBM cancer stem cell signature is enriched in cognate human GBM cells • A 118-gene signature including F3 identifies quiescent human cancer stem cells • Quiescent GBM cancer stem cells become activated upon chemotherapy Tumor recurrence is a challenge in glioblastoma (GBM) treatment. Xie, Laks et al. characterize quiescent cancer stem cells, in both mouse and human GBM, that become activated upon chemotherapy, thus paving the way for interrogation of the cancer stem cell role in GBM recurrence and the identification of potentially actionable vulnerabilities. [ABSTRACT FROM AUTHOR]