PO-334 Identification of shared lineage programs across high-grade glioma subtypes by single-cell RNA-seq

Abstract

IntroductionIn glioblastoma (GBM), a subset of stem-like cells that have the ability to propagate tumours underlie therapeutic resistance. Stem-like cells with either astrocytic or oligodendrocytic phenotypes have been described. However, the full complement of cell types found in gliomas and their lineage relationship to these progenitors is unknown.Material and methodsWe profiled the transcriptomes of ~30 000 single cells from 12 primary GBM biopsies via single-cell RNA sequencing (scRNA-seq) using the 10x Genomics and Fluidigm C1 platforms.Results and discussionsUnsupervised clustering revealed two recurrent transcriptional programs associated with either the astrocytic (e.g. AQP4, CLU, GFAP) or oligodendrocytic (e.g. HES6, OLIG1, OLIG2) lineages. Principle component analyses within these cell groups revealed differentiation gradients. Stemness markers CD44 and CHI3L1 mark the apex of the astrocytic lineage, while OLIG2 and PDGFRA mark the apex of the oligodendrocytic lineage. Conversely, markers of differentiated astrocytes such as ALDOC and of differentiated oligodendrocytes such as TMSB4X were enriched at the trunk of the respective lineages. We found these two lineage hierarchies in most tumours, indicating a co-evolution of glioma cells from two independent stem cell populations within the same tumour. High expression of hypoxic markers (ADM, EPAS1, VEGFA) was almost exclusively found in astrocyte-like cells. While oligodendrocyte progenitor cell (OPC)-like cells were mostly actively cycling, astrocytic stem cells were mostly quiescent.ConclusionOur study sheds light on intra-tumour heterogeneity and lineage relationship. Given that GBMs are composed of cells resembling the astrocytic and cells resembling the oligodendrocytic lineage suggests that combined therapy targeting stem-like cells from both populations might be effective in GBM treatment.