Adult-type diffuse gliomas share recurring cell states driven by a common astrocyte-like glioma stem cell population

Abstract

Summary Adult-type diffuse gliomas are a family of aggressive brain tumours with few effective treatments. Their complex cellular makeup adds to the challenge of finding successful therapies. This intratumoural heterogeneity is fuelled by a subpopulation of glioma stem-like cells (GSCs) that drive tumour growth and resistance to standard treatments. Previous research focused on the three glioma types (astrocytoma, oligodendroglioma, glioblastoma) individually revealed malignant cells mimic the transcriptional profiles of normal brain cell types. Whether these diverse cellular states stem from a shared biological origin is unknown. Here, we show through single-cell RNA sequencing of 40 glioma tumours that all gliomas are described by seven recurring cell states. We also identify a shared astrocyte-like GSC population. Our unique method of identifying GSCs, based on reconstructed tumour phylogenies, repositions astrocyte-like cells at the apex of a differentiation hierarchy in glioma. Our findings indicate the transcriptional heterogeneity observed in gliomas stems from a GSC population recapitulating lineages of healthy adult neural stem cells. These results suggest a shared lineage drives the intratumoural heterogeneity observed in adult-type diffuse gliomas. We anticipate that a deeper understanding of the molecular mechanisms maintaining the GSC state will provide a new framework for future therapeutic development and research into glioma cell biology. Highlights Recurring cell states are shared across adult-type diffuse gliomas Reconstructed tumour phylogenies identify an astrocyte-like glioma stem cell population Tumour subclones are segregated non-randomly across cell states