SOX10 mediates glioblastoma cell-state plasticity

• Published in: EMBO reports 2024-11, Vol.25 (11), p.5113-5140
• Main Authors: Man, Ka-Hou, Wu, Yonghe, Gao, Zhenjiang, Spreng, Anna-Sophie, Keding, Johanna, Mangei, Jasmin, Boskovic, Pavle, Mallm, Jan-Philipp, Liu, Hai-Kun, Imbusch, Charles D, Lichter, Peter, Radlwimmer, Bernhard
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Line, Tumor; Cell Plasticity - drug effects; Cell Plasticity - genetics; EMBO03; EMBO34; Gene Expression Regulation, Neoplastic; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Life Sciences; Mice; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; Receptors, Notch - genetics; Receptors, Notch - metabolism; Signal Transduction; Single-Cell Analysis; SOXE Transcription Factors - genetics; SOXE Transcription Factors - metabolism; Temozolomide - pharmacology
• ISSN: 1469-3178; 1469-221X; 1469-3178
• DOI: 10.1038/s44319-024-00258-8

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. Synopsis This study examines SOX10-dependent cell-state transitions in glioblastoma and uses single-cell analyses to design a combination therapy that extends survival in an immunocompetent glioblastoma mouse model. SOX10 suppression reprograms glioblastoma towards an aggressive Neural-Stem-Cell/Developmental-like phenotype, including a slow-cycling, quiescent stem cell-like cell state. Combination treatment targeting slow-cycling stem cells and proliferating cells extends survival in a syngeneic glioblastoma in vivo model. This study examines SOX10-dependent cell-state transitions in glioblastoma and uses single-cell analyses to design a combination therapy that extends survival in an immunocompetent glioblastoma mouse model.