Targeting Cystine Addiction Suppresses Breast Cancer Lung Metastasis

Abstract Metastatic disease remains a major cause of cancer-related mortality. Recent studies suggest that dissemination to other organs comes with metabolic changes that allow the metastasizing cancer cells to adapt to new microenvironments. A deeper knowledge of these specific metabolic features and associated vulnerabilities could lead to the development of more effective therapies against metastasis. We used in vivo and ex vivo models of MYC-driven breast tumorigenesis to explore the key metabolic pathways that change when mammary gland tumor (MGT) cells metastasize to the lung. Stable isotope-resolved metabolomics, mass spectrometry imaging, and single-cell RNA sequencing demonstrated that MGT-derived lung metastases have increased synthesis of glutathione fueled by increased cystine uptake. Metastatic cells relied heavily on the availability of extracellular cysteine or cystine, possibly due to downregulated intracellular cysteine synthesis through the transsulfuration pathway. When combined with focal radiotherapy, the amino acid degrader cyst(e)inase effectively reduced metastatic burden in the lungs. Together, these findings show that targeting cystine/cysteine exploits a metabolic dependency that is unique to metastatic cells and acts as a sensitizer to radiotherapy-induced oxidative stress, offering a promising targeted strategy. Significance: A radiotherapy-sensitizing combination with the amino acid degrader cyst(e)inase is an effective strategy to treat breast metastasis to the lungs, tackling the specific dependence of metastatic cells on cysteine and cystine.