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 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.

Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer.

Chromosome instability (CIN) contributes to resistance to therapies and tumor evolution. Although natural killer (NK) cells can eliminate cells with complex karyotypes, high-CIN human tumors have an immunosuppressive phenotype. To understand which CIN-associated molecular features alter immune recognition during tumor evolution, we overexpress Polo-like kinase 1 (Plk1) in a Her2+ breast cancer model. These high-CIN tumors activate a senescence-associated secretory phenotype (SASP), upregulate PD-L1 and CD206, and induce non-cell-autonomous nuclear factor κB (NF-κß) signaling, facilitating immune evasion. Single-cell RNA sequencing from pre-neoplastic mammary glands unveiled the presence of Arg1+ macrophages, NK cells with reduced effector functions, and increased resting regulatory T cell infiltration. We further show that high PLK1-expressing human breast tumors display gene expression patterns associated with SASP, NF-κß signaling, and immune suppression. These findings underscore the need to understand the immune landscape in CIN tumors to identify more effective therapies, potentially combining immune checkpoint or NF-κß inhibitors with current treatments.