2025-08-15 ロックフェラー大学
Spatial metablomic imaging of glutathione in a mouse lung with metastases. (Birsoy lab)
<関連情報>
- https://www.rockefeller.edu/news/38146-mitochondrial-antioxidant-found-to-drive-breast-cancer-metastasis/
- https://aacrjournals.org/cancerdiscovery/article-abstract/doi/10.1158/2159-8290.CD-24-1556/763897/Mitochondrial-glutathione-import-enables-breast?redirectedFrom=fulltext
ミトコンドリアのグルタチオン輸入は、統合ストレス応答シグナル伝達を介して乳がん転移を促進する Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling
Hsi-wen Yeh;Nicole Lauren. DelGaudio;Beste Uygur;Alon Millet;Artem Khan;Gokhan Unlu;Michael Xiao;Rebecca C. Timson;Caifan Li;Kerem Ozcan;Karl W. Smith;Luiza Martins. Nascentes Melo;Gabriele Allies;Olca Basturk;Albert Sickmann;Erol C. Bayraktar;Richard Possemato;Alpaslan Tasdogan;Kivanc Birsoy
Cancer Discovery Published:July 31 2025
DOI:https://doi.org/10.1158/2159-8290.CD-24-1556
Abstract
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.
