Ottawa Institute of Systems Biology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
Sci Adv. 2024 Nov 8;10(45):eadm8212. doi: 10.1126/sciadv.adm8212. Epub 2024 Nov 6.
Mitochondrial dynamics orchestrate many essential cellular functions, including metabolism, which is instrumental in promoting cancer growth and metastatic progression. However, how mitochondrial dynamics influences metastatic progression remains poorly understood. Here, we show that breast cancer cells with low metastatic potential exhibit a more fused mitochondrial network compared to highly metastatic cells. To study the impact of mitochondrial dynamics on metastasis, we promoted mitochondrial elongation in metastatic breast cancer cells by individual genetic deletion of three key regulators of mitochondrial fission (Drp1, Fis1, Mff) or by pharmacological intervention with leflunomide. Omics analyses revealed that mitochondrial elongation causes substantial alterations in metabolic pathways and processes related to cell adhesion. In vivo, enhanced mitochondrial elongation by loss of mitochondrial fission mediators or treatment with leflunomide notably reduced metastasis formation. Furthermore, the transcriptomic signature associated with elongated mitochondria correlated with improved clinical outcome in patients with breast cancer. Overall, our findings highlight mitochondrial dynamics as a potential therapeutic target in breast cancer.
线粒体动态调控许多重要的细胞功能，包括代谢，这对于促进癌症生长和转移进展至关重要。然而，线粒体动态如何影响转移进展仍知之甚少。在这里，我们发现低转移潜能的乳腺癌细胞与高转移细胞相比，线粒体网络更为融合。为了研究线粒体动力学对转移的影响，我们通过单独遗传缺失三个关键的线粒体分裂调节因子（Drp1、Fis1、Mff）或用来氟米特进行药物干预，促进转移性乳腺癌细胞中线粒体的伸长。组学分析显示，线粒体伸长导致代谢途径和与细胞黏附相关的过程发生显著改变。在体内，通过缺失线粒体分裂介质或用来氟米特增强线粒体伸长，显著减少了转移的形成。此外，与伸长线粒体相关的转录组特征与乳腺癌患者的临床预后改善相关。总的来说，我们的研究结果强调了线粒体动态作为乳腺癌潜在治疗靶点的重要性。
