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

Charles Couturier ,Jack Antel,Changseok Lee,Yu Chang David Wang,Phuong Uyen Le ,Redouane Allache,V Wee Yong,Marie‐Christine Guiot ,Shamini Ayyadhury,Mathieu Bourgey,Jean Monlong,Gabriele Riva,Hamed S Najafabadi ,Javad Nadaf,Salma Baig,Bratislav Mišić ,Guillaume Bourque,Xiaohua Yan,Jiannis Ragoussis,Kevin Petrecca

doi:10.1038/s41467-020-17186-5

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.

Highlights

Cancer stem cells are critical for cancer initiation, development, and treatment resistance
A neurodevelopmental bi-lineage hierarchy has been shown to explain a portion of this heterogeneity in IDH mutant glioma[24,25] and high-grade pediatric glioma[26], this has not been possible in adult IDH wild-type (IDHwt) glioblastoma
When enriched glioblastoma stem cells (GSCs) and whole-tumor cells were sequenced from the same patient, these samples clustered together (Fig. 1a and Supplementary Fig. 1f)

Summary

Introduction

Cancer stem cells are critical for cancer initiation, development, and treatment resistance. It has been shown that multiple subtypes coexist in different regions[21,22] and different cells[12,20] within the same tumor This interpatient and intratumoral heterogeneity poses a daunting challenge for research programs aimed at developing targeted therapeutic approaches[23] and may explain the failures of such approaches in this disease. A neurodevelopmental bi-lineage hierarchy has been shown to explain a portion of this heterogeneity in IDH mutant glioma[24,25] and high-grade pediatric glioma[26], this has not been possible in adult IDHwt glioblastoma Another layer of complexity was uncovered by the discovery of a small subpopulation of glioblastoma cells that have stem-like properties[13,14]. These data suggest that GSCs may have a role in cancer development and recurrence

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Methods

Results