Yeh Hsi-Wen, DelGaudio Nicole Lauren, Uygur Beste, Millet Alon, Khan Artem, Unlu Gokhan, Xiao Michael, Timson Rebecca C, Li Caifan, Ozcan Kerem, Smith Karl W, Nascentes Melo Luiza Martins, Allies Gabriele, Basturk Olca, Sickmann Albert, Bayraktar Erol C, Possemato Richard, Tasdogan Alpaslan, Birsoy Kivanc
Rockefeller University, New York, New York, United States.
Rockefeller University, United States.
Cancer Discov. 2025 Jul 31. doi: 10.1158/2159-8290.CD-24-1556.
Cancer cells require substantial metabolic adaptations to metastasize to distant organs, but the metabolites essential for successful colonization remain poorly defined. Here, we used a mitochondrial metabolomics approach to compare primary and metastatic breast cancer cells. This analysis revealed accumulation of mitochondrial glutathione (GSH) during lung metastasis, driven by elevated expression of SLC25A39, a mitochondrial GSH transporter. Loss of SLC25A39 impairs metastatic colonization in genetic screens, cell line models, and patient-derived xenografts, without affecting primary tumor growth. Mitochondrial GSH import is specifically required during early colonization and functions independently of its canonical antioxidant role. CRISPR activation screens identified ATF4, a stress-induced transcription factor, as a bypass mechanism that restores metastatic potential in SLC25A39-deficient cells. Mechanistically, SLC25A39 is required for optimal ATF4 activation during metastasis and under hypoxia, linking mitochondrial GSH availability to integrated stress response signaling. These findings identify mitochondrial GSH as a necessary and limiting metabolite for metastatic progression.
癌细胞需要大量的代谢适应才能转移到远处器官，但成功定植所必需的代谢物仍不清楚。在这里，我们使用线粒体代谢组学方法比较原发性和转移性乳腺癌细胞。该分析揭示了在肺转移过程中线粒体谷胱甘肽（GSH）的积累，这是由线粒体GSH转运体SLC25A39的表达升高驱动的。在基因筛选、细胞系模型和患者来源的异种移植中，SLC25A39的缺失会损害转移性定植，但不影响原发性肿瘤的生长。线粒体GSH的导入在早期定植过程中是特别需要的，并且其功能独立于其典型的抗氧化作用。CRISPR激活筛选确定了应激诱导转录因子ATF4是一种旁路机制，可恢复SLC25A39缺陷细胞的转移潜力。从机制上讲，SLC25A39是转移过程中和缺氧条件下最佳ATF4激活所必需的，将线粒体GSH的可用性与综合应激反应信号联系起来。这些发现确定线粒体GSH是转移进展所必需的且有限的代谢物。
