Background

Mitochondrial dynamics play a fundamental role in determining stem cell fate. However, the underlying mechanisms of mitochondrial dynamics in the stemness acquisition of cancer cells are incompletely understood.

Methods

Metabolomic profiling of cells were analyzed by MS/MS. The genomic distribution of H3K27me3 was measured by CUT&Tag. Oral squamous cell carcinoma (OSCC) cells depended on glucose or glutamine fueling TCA cycle were monitored by 13C-isotope tracing. Organoids and tumors from patients and mice were treated with DRP1 inhibitors mdivi-1, ferroptosis inducer erastin, or combination with mdivi-1 and erastin to evaluate treatment effects.

Results

Mitochondria of OSCC stem cells own fragment mitochondrial network and DRP1 is required for maintenance of their globular morphology. Imbalanced mitochondrial dynamics induced by DRP1 knockdown suppressed stemness of OSCC cells. Elongated mitochondria increased α-ketoglutarate levels and enhanced glutaminolysis to fuel the TCA cycle by increasing glutamine transporter ASCT2 expression. α-KG promoted the demethylation of histone H3K27me3, resulting in downregulation of SNAI2 associated with stemness and EMT. Significantly, suppressing DRP1 enhanced the anticancer effects of ferroptosis.

Conclusion

Our study reveals a novel mechanism underlying mitochondrial dynamics mediated cancer stemness acquisition and highlights the therapeutic potential of mitochondria elongation to increase the susceptibility of cancer cells to ferroptosis.

中文翻译：

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DRP1 抑制介导的线粒体伸长消除了口腔鳞状细胞癌中的癌症干细胞性、增强谷氨酰胺分解并驱动铁死亡

背景

线粒体动力学在决定干细胞命运中发挥着重要作用。然而，线粒体动力学在癌细胞干性获得中的潜在机制尚不完全清楚。

方法

通过 MS/MS 分析细胞的代谢组学谱。通过CUT&Tag测量H3K27me3的基因组分布。通过 13C 同位素示踪监测依赖葡萄糖或谷氨酰胺为 TCA 循环提供燃料的口腔鳞状细胞癌 (OSCC) 细胞。使用 DRP1 抑制剂 mdivi-1、铁死亡诱导剂erastin 或 mdivi-1 与erastin 联合治疗来自患者和小鼠的类器官和肿瘤，以评估治疗效果。

结果

OSCC干细胞的线粒体拥有线粒体网络片段，DRP1是维持其球状形态所必需的。 DRP1 敲低诱导的线粒体动力学失衡抑制了 OSCC 细胞的干性。延长的线粒体增加了 α-酮戊二酸水平并增强了谷氨酰胺分解，通过增加谷氨酰胺转运蛋白 ASCT2 表达来为 TCA 循环提供燃料。 α-KG 促进组蛋白 H3K27me3 去甲基化，导致与干性和 EMT 相关的 SNAI2 下调。值得注意的是，抑制 DRP1 增强了铁死亡的抗癌作用。

结论

我们的研究揭示了线粒体动力学介导癌症干性获得的新机制，并强调了线粒体伸长在增加癌细胞对铁死亡的易感性方面的治疗潜力。