Single-Cell Chromatin Accessibility Profiling of Glioblastoma Identifies an Invasive Cancer Stem Cell Population Associated With Lower Survival
Chromatin accessibility discriminates stem from mature cell populations, enabling the identification of primitive stem-like cells in primary tumours, such as glioblastoma (GBM) where self-renewing cells driving cancer progression and recurrence are prime targets for therapeutic intervention. We show, using single-cell chromatin accessibility, that primary human GBMs harbour a heterogeneous self-renewing population whose diversity is captured in patient-derived glioblastoma stem cells (GSCs). In-depth characterization of chromatin accessibility in GSCs identifies three GSC states: Reactive, Constructive, and Invasive, each governed by uniquely essential transcription factors and present within GBMs in varying proportions. Orthotopic xenografts reveal that GSC states associate with survival, and identify an invasive GSC signature predictive of low patient survival, in line with the higher invasive properties of Invasive state GSCs compared to Reactive and Constructive GSCs as shown by in vitro and in vivo assays. Our chromatin-driven characterization of GSC states improves prognostic precision and identifies dependencies to guide combination therapies.
Keywords: ATAC; Glioblastoma; cancer biology; cancer stem cell; chromatin; human; single-cell ATAC; tumour initiating cells