Targeting cystine addiction to treat breast cancer lung metastasis
File(s)
Author(s)
Burt, Richard
Tarrago-Celada, Josep
Yuneva, Mariia
Type
Journal Article
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 metastasising 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 tumour cells metastasise 50
to the lung. By stable isotope-resolved metabolomics, mass spectrometry imaging and single-cell RNA sequencing we demonstrate that mammary gland tumour-derived lung metastases have increased synthesis of glutathione fuelled by increased cystine uptake. Our results uncover that metastatic cells rely heavily on the availability of extracellular cysteine or cystine, possibly due to downregulated intracellular cysteine synthesis through transsulfuration pathway. Based on this finding of cysteine/cystine addiction, we show that when combined with focal radiotherapy, the amino acid degrader cyst(e)inase can effectively reduce metastatic burden in the lungs. This novel combinatorial approach exploits a metabolic dependency that is unique to the metastatic cells, and acts as a sensitizer to
radiotherapy-induced oxidative stress, offering a promising targeted strategy.
Statement of significance
In this work we propose a new radio therapy-sensitizing combination with the amino acid degrader Cyst(e)inase to treat breast cancer metastasis to the lung, tackling the specific dependence of metastatic cells on cysteine and cystine.
to the lung. By stable isotope-resolved metabolomics, mass spectrometry imaging and single-cell RNA sequencing we demonstrate that mammary gland tumour-derived lung metastases have increased synthesis of glutathione fuelled by increased cystine uptake. Our results uncover that metastatic cells rely heavily on the availability of extracellular cysteine or cystine, possibly due to downregulated intracellular cysteine synthesis through transsulfuration pathway. Based on this finding of cysteine/cystine addiction, we show that when combined with focal radiotherapy, the amino acid degrader cyst(e)inase can effectively reduce metastatic burden in the lungs. This novel combinatorial approach exploits a metabolic dependency that is unique to the metastatic cells, and acts as a sensitizer to
radiotherapy-induced oxidative stress, offering a promising targeted strategy.
Statement of significance
In this work we propose a new radio therapy-sensitizing combination with the amino acid degrader Cyst(e)inase to treat breast cancer metastasis to the lung, tackling the specific dependence of metastatic cells on cysteine and cystine.
Date Acceptance
2026-04-10
Citation
Cancer Research
ISSN
0008-5472
Publisher
American Association for Cancer Research
Journal / Book Title
Cancer Research
Copyright Statement
Copyright This paper is embargoed until publication. Once published the author’s accepted manuscript will be made available under a CC-BY License in accordance with Imperial’s Research Publications Open Access policy (www.imperial.ac.uk/oa-policy).
License URL
Publication Status
Accepted
Date Publish Online
2026-04-29