TY  - JOUR
AU  - Man, Ka Hou
AU  - Wu, Yonghe
AU  - Gao, Zhenjiang
AU  - Spreng, Anna-Sophie
AU  - Keding, Sigrun Johanna Elisabeth
AU  - Mangei, Jasmin
AU  - Boskovic, Pavle
AU  - Mallm, Jan-Philipp
AU  - Liu, Hai-Kun
AU  - Imbusch, Charles D
AU  - Lichter, Peter
AU  - Radlwimmer, Bernhard
TI  - SOX10 mediates glioblastoma cell-state plasticity.
JO  - EMBO reports
VL  - 25
IS  - 11
SN  - 1469-221X
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DKFZ-2024-01877
SP  - 5113-5140
PY  - 2024
N1  - #EA:B060#LA:B060# / 2024 Nov;25(11):5113-5140
AB  - 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.
KW  - SOX10 (Other)
KW  - Glioblastoma (Other)
KW  - Phenotypic Plasticity (Other)
KW  - Therapy Resistance (Other)
KW  - Tumor Cell Quiescence (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:39285246
DO  - DOI:10.1038/s44319-024-00258-8
UR  - https://inrepo02.dkfz.de/record/293327
ER  -