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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 18975 |
| Tidsskrift | Scientific Reports |
| Vol/bind | 12 |
| Antal sider | 18 |
| ISSN | 2045-2322 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:The research was generally supported by Russian Science Foundation (RSF) Grant 20-15-00378. V.G. was previously funded by a grant from the President of the Russian Federation for the 2018/2019 academic year of the Ministry of Science and Higher Education of the Russian Federation, which was very useful for developing a single-nucleus transcriptomics technique and adapting it to the goals of this work.
Funding Information:
We would like to thank Ulrich Pfisterer and Mykhailo Batiuk from BRIC (University of Copenhagen) for assistance with handling single nucleus experiments and advices. We thank BRIC’s single-cell core facility and Anna Fossum from BRIC’s flow-cytometry core facility for technical assistance. The data analysis was performed using computing power provided by Vladimir Goy from the School of Natural Sciences of Far Eastern Federal University. Additionally, we appreciate the scientific feedback on the current manuscript provided by Stanislav Rybtsov (MRC Centre for Regenerative Medicine: Edinburgh, Edinburgh, GB), Yuri Panchin (Lomonosov Moscow State University, Moscow, Russia), Vladimir Katanaev (Chair in Translational Oncology, University of Geneva, Geneva, Switzerland).
Publisher Copyright:
© 2022, The Author(s).