SOX10介导胶质母细胞瘤细胞状态的可塑性。

IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Reports Pub Date : 2024-11-01 Epub Date: 2024-09-16 DOI:10.1038/s44319-024-00258-8
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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引用次数: 0

摘要

表型可塑性是胶质母细胞瘤治疗失败的原因之一。我们以前的研究表明,抑制少突胶质细胞系调节因子SOX10会促进胶质母细胞瘤的进展。在这里,我们分析了SOX10介导的表型可塑性,并利用它来设计胶质母细胞瘤疗法。我们发现,SOX10的低表达与神经干细胞(NSC)样胶质母细胞瘤细胞状态有关,并且是动物和细胞系模型中替莫唑胺治疗的结果。Sox10-KD肿瘤的单细胞转录组分析表明,Sox10抑制足以诱导肿瘤发展为侵袭性NSC/发育样表型,包括静止NSC样细胞群。在细胞系模型中,替莫唑胺和Sox10-KD会诱导静止NSC状态,而Notch通路抑制则会降低这种状态。Notch和HDAC/PI3K抑制剂的联合治疗延长了携带Sox10-KD肿瘤的小鼠的生存期,验证了我们的实验治疗方法。总之,SOX10抑制通过NSC/发育细胞状态转换介导胶质母细胞瘤的进展,包括诱导可靶向的静止NSC状态。这项工作为基于单细胞表型可塑性分析设计肿瘤疗法提供了理论依据。
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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 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.

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来源期刊
EMBO Reports
EMBO Reports 生物-生化与分子生物学
CiteScore
11.20
自引率
1.30%
发文量
267
审稿时长
1 months
期刊介绍: EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry. 
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