Single-nucleus transcriptomics of IDH1- and TP53-mutant glioma stem cells displays diversified commitment on invasive cancer progenitors

Abstract

Abstract Glioma is a devastating brain tumor with a high mortality rate attributed to the glioma stem cells (GSCs) possessing high plasticity. Marker mutations in isocitrate dehydrogenase type 1 (IDH1) and tumor protein 53 (TP53) are frequent in gliomas and impact the cell fate decisions. Understanding the GSC heterogeneity within IDH1- and TP53- mutant tumors may elucidate possible treatment targets. Here, we performed single-nucleus transcriptomics of mutant and wild-type glioma samples sorted for Sox2 stem cell marker. For the first time the rare subpopulations of Sox2 + IDH1- and TP53-mutant GSCs were characterized. In general, GSCs contained the heterogeneity root subpopulation resembling active neural stem cells capable of asymmetric division to quiescent and transit amplifying cell branches. Specifically, double-mutant GSCs revealed the commitment on highly invasive oligodendrocyte- and astroglia-like progenitors. Additionally, double-mutant GSCs displayed upregulated markers of collagen synthesis, altered lipogenesis and high migration, while wild-type GSCs expressed genes related to ATP production. Wild-type GSC root population was highly heterogeneous and lacked the signature marker expression, thus glioblastoma treatment should emphasize on establishing differentiation protocol directed against residual GSCs. For the more differentiated IDH1- and TP53-mutant gliomas we suggest therapeutic targeting of migration molecules, such as CD44.