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SOX10 mediates glioblastoma cell-state plasticity

Phenotypic plasticity is a cause of glioblastoma therapy failure. We previously showed that suppressing the oligodendrocyte-lineage regulator SOX10 promotes glioblastoma progression. Here, we analyze SOX10-mediated phenotypic plasticity and exploit it for glioblastoma therapy design. We show that lo...

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Main Authors: Man, Ka-Hou (Author) , Wu, Yonghe (Author) , Gao, Zhenjiang (Author) , Spreng, Anna-Sophie (Author) , Keding, Johanna (Author) , Mangei, Jasmin (Author) , Boskovic, Pavle (Author) , Mallm, Jan-Philipp (Author) , Liu, Hai-Kun (Author) , Imbusch, Charles (Author) , Lichter, Peter (Author) , Radlwimmer, Bernhard (Author)
Format: Article (Journal)
Language:English
Published: 16 September 2024
In: EMBO reports
Year: 2024, Volume: 25, Issue: 11, Pages: 5113-5140
ISSN:1469-3178
DOI:10.1038/s44319-024-00258-8
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s44319-024-00258-8
Verlag, kostenfrei, Volltext: https://www.embopress.org/doi/full/10.1038/s44319-024-00258-8
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Author Notes:Ka-Hou Man, Yonghe Wu, Zhenjiang Gao, Anna-Sophie Spreng, Johanna Keding, Jasmin Mangei, Pavle Boskovic, Jan-Philipp Mallm, Hai-Kun Liu, Charles D Imbusch, Peter Lichter & Bernhard Radlwimmer
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Summary:Phenotypic plasticity is a cause of glioblastoma therapy failure. We previously showed that suppressing the oligodendrocyte-lineage regulator SOX10 promotes glioblastoma progression. Here, we analyze SOX10-mediated phenotypic plasticity and exploit it for glioblastoma therapy design. We show that low SOX10 expression is linked to neural stem-cell (NSC)-like glioblastoma cell states and is a consequence of temozolomide treatment in animal and cell line models. Single-cell transcriptome profiling of Sox10-KD tumors indicates that Sox10 suppression is sufficient to induce tumor progression to an aggressive NSC/developmental-like phenotype, including a quiescent NSC-like cell population. The quiescent NSC state is induced by temozolomide and Sox10-KD and reduced by Notch pathway inhibition in cell line models. Combination treatment using Notch and HDAC/PI3K inhibitors extends the survival of mice carrying Sox10-KD tumors, validating our experimental therapy approach. In summary, SOX10 suppression mediates glioblastoma progression through NSC/developmental cell-state transition, including the induction of a targetable quiescent NSC state. This work provides a rationale for the design of tumor therapies based on single-cell phenotypic plasticity analysis.
Item Description:Gesehen am 03.03.2025
Physical Description:Online Resource
ISSN:1469-3178
DOI:10.1038/s44319-024-00258-8

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