RT Journal Article
SR Electronic
T1 A single-cell atlas of human glioblastoma reveals a single axis of phenotype in tumor-propagating cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 377606
DO 10.1101/377606
A1 Sören Müller
A1 Elizabeth Di Lullo
A1 Aparna Bhaduri
A1 Beatriz Alvarado
A1 Garima Yagnik
A1 Gary Kohanbash
A1 Manish Aghi
A1 Aaron Diaz
YR 2018
UL http://biorxiv.org/content/early/2018/07/26/377606.abstract
AB Tumor-propagating glioblastoma (GBM) stem-like cells (GSCs) of the proneural and mesenchymal molecular subtypes have been described. However, it is unknown if these two GSC populations are sufficient to generate the spectrum of cellular heterogeneity observed in GBM. The lineage relationships and niche interactions of GSCs have not been fully elucidated. We perform single-cell RNA-sequencing (scRNA-seq) and matched exome sequencing of human GBMs (12 patients; >37,000 cells) to identify recurrent hierarchies of GSCs and their progeny. We map sequenced cells to tumor-anatomical structures and identify microenvironment interactions using reference atlases and quantitative immunohistochemistry. We find that all GSCs can be described by a single axis of variation, ranging from proneural to mesenchymal. Increasing mesenchymal GSC (mGSC) content, but not proneural GSC (pGSC) content, correlates with significantly inferior survival. All clonal expressed mutations are found in the GSC populations, with a greater representation of mutations found in mGSCs. While pGSCs upregulate markers of cell-cycle progression, mGSCs are largely quiescent and overexpress cytokines mediating the chemotaxis of myeloid-derived suppressor cells. We find mGSCs enriched in hypoxic regions while pGSCs are enriched in the tumor’s invasive edge. We show that varying proportions of mGSCs, pGSCs, their progeny and stromal/immune cells are sufficient to explain the genetic and phenotypic heterogeneity observed in GBM. This study sheds light on a long-standing debate regarding the lineage relationships between GSCs and other glioma cell types.