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

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.

WITHDRAWN: LonP1 Drives Proneural Mesenchymal Transition in IDH1-R132H Diffuse Glioma

“…The following datasets were accessed: GSE84465 36 , GSE131928 37 , GSE164624 38 , GSE151506 39 and GSE117891 40 . The counts data from each dataset was used to reassign cell types using scSorter 41 with the following markers used to identify Neoplastic (e.g.…”

“…FOXM1) induced by chemotherapy 50 . Here, we merged several single cell RNA sequencing datasets (GSE84465 36 , GSE131928 37 , GSE164624 38 , GSE151506 39 and GSE117891 40 ) into a library comprising of samples with different grades, IDH1 mutation status and other features to perform hdWGCNA analysis. The UMAP following harmonization shows clear separation of distinct cell types (Fig.…”

Nanomechanical Signatures in Glioma Cells Depend on CD44 Distribution in IDH1 Wild-Type but Not in IDH1R132H Mutant Early-Passage Cultures

“…Glioma stem cells exhibit an increased level of CD44 [ 45 ]. In addition to that, our recent data, obtained by single nucleus transcriptomics of glioma stem cells captured from tumor samples by sorting for Sox2 positive nuclei, demonstrated that IDH1 R132H migrating astrocyte-precursor cells are characterized by the highest CD44 expression among different subpopulations of glioma stem cells [ 46 ].…”

“…We attempted to determine nanomechanical profiles that are characteristic for the investigated cell phenotypes. The increased stiffness and Young’s modulus of the IDH1 R132H mutant cells turned out to be highly indicative, which is probably mediated by both altered cytoskeleton and lipogenesis in mutant cells [ 24 , 46 , 61 ]. In this work, we first used the early-passage glioma cell cultures to compare hardness of IDH1 R132H mutant and IDH1 wild-type cells.…”

Characterization of a lactate metabolism-related signature for evaluation of immune features and prediction prognosis in glioma

“…Our study illustrated that patients with glioma in the two risk groups had distinct genetic alterations, activated pathways, and potentially sensitive drugs. A common characteristic of gliomas is the presence of markers for IDH1 and TP53 mutations, which influence the fate of the cells ( 42 ). The two risk groups were IDH1- and TP53-dominant mutations, respectively, suggesting discrepant oncogenesis mechanisms.…”