Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy

TLDR

Cancer stem cells drive initiation, progression, and resistance, yet their role in glioblastoma heterogeneity remains poorly understood. The study aimed to compare single‑cell transcriptomes of glioblastoma and fetal brain to map lineage hierarchies. Using single‑cell RNA‑seq of 53,586 glioblastoma cells and 22,637 fetal brain cells, the authors compared developmental lineage hierarchies to cancer transcriptomes. A conserved neural tri‑lineage hierarchy centered on glial progenitor‑like cells was identified, with this progenitor population driving most cycling cells and giving rise to other types; the map enables identification of progenitor‑specific therapeutic targets and links glioblastoma development to normal neurodevelopment.

Abstract

Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer's cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets.