SOX10 controls glioblastoma cell state plasticity and progression

Phenotypic plasticity is a significant cause of glioblastoma therapy failure. We previously showed that suppressing the oligodendrocyte-lineage regulator SOX10 promotes glioblastoma progression. Here, we analyzed SOX10-mediated phenotypic plasticity and exploited it for glioblastoma therapy design. We demonstrated 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 indicated 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 was induced by temozolomide and Sox10-KD and depleted by Notch pathway inhibition in cell line models. Combination treatment using Notch and HDAC/PI3K inhibitors significantly extended 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.