Dortmund, 14th August 2026
In breast cancer, it is often not the original tumour that poses the greatest risk, but the spread of tumour cells to other organs like the lungs. In this environment, the cells initially encounter poor conditions for survival: a lack of nutrients, increased oxidative stress and the tissue’s defence mechanisms make it difficult to survive. However, a small proportion of tumour cells manage to adapt to the new environment, grow and form metastases. A study published in the journal Cancer Discovery, involving researchers from ISAS, shows that the endogenous antioxidant glutathione plays a crucial role in this process.
The researchers from Rockefeller University, New York University, Memorial Sloan Kettering Cancer Center, University Hospital Essen, and ISAS compared breast cancer cells from primary tumours and lung metastases in vitro using cultured cancer cells from human and mice. They specifically analysed metabolic processes in the mitochondria. The metastatic cells exhibited significantly higher levels of mitochondrial glutathione.
Glutathione serves to protect cells from oxidative stress (see info box). However, in the context of cancer, this protective function can have adverse effects: tumour cells exploit this mechanism to become more resilient. They activate a metabolic adaptation programme that facilitates their survival in new organs and promotes the formation of metastases.
Dr Karl Smith is Head of the Spatial Metabolomics junior research group.
© ISAS
ATF4 activates a survival programme in tumour cells
“Using MALDI mass spectrometry imaging, we were able to detect glutathione in tumour tissue with spatial resolution and identify where it accumulates most within the metastasized organ,” explains Dr Karl Smith, head of the Spatial Metabolomics junior research group. To this end, Smith and his team analysed lung tissue from mice with breast cancer metastases. Glutathione in the mitochondria acts as a signal for the protein ATF4. The latter regulates key genes involved in stress and metabolic responses, thereby activating the tumour cells’ survival mechanisms. The cells adapt their metabolism to the new environment, enabling them to establish themselves in lung tissue – a crucial prerequisite for metastasis formation.
Glutathione: cellular protection and metabolic balance
Glutathione is a tripeptide produced naturally by the body, consisting of the amino acids glycine, cysteine and glutamic acid. It is one of the most important antioxidants within cells and protects them from oxidative stress. Oxidative stress refers to a metabolic imbalance in which too many free radicals (reactive oxygen molecules) encounter too few protective antioxidants. This can damage cells. Oxidative stress is linked to the development of various diseases, including cancer. Glutathione helps to maintain metabolic balance and stabilise key cellular functions.
Transport protein as a key to new therapies?
The authors identified the protein SLC25A39 as a key component of the processes described. It is located in the mitochondrial membrane and acts as a transport protein for glutathione. The findings show that metastatic breast cancer cells produce increased levels of SLC25A39. They require this transport protein to adapt to new tissue. If SLC25A39 is switched off, less glutathione enters the mitochondria. Consequently, fewer metastases form. The growth of the primary tumour remains largely unaffected. This phenomenon is particularly pronounced in the early phase of metastasis, when tumour cells settle in the lungs and need to adapt to the new tissue environment.
The study reveals that tumor cells activate specific adaptation and survival mechanisms to successfully establish themselves in new tissues. The SLC25A39 protein is therefore emerging as a potential therapeutic target. If this transport protein could be specifically inhibited, it could regulate the import of glutathione into the mitochondria and prevent tumour cells from successfully establishing themselves in the new tissue. In the long term, this could lead to potential new therapeutic strategies specifically aimed at slowing down or preventing the spread of breast cancer in the body.
(Saskia Schlesinger)
Article Recommendation
Yeh, H.W., DelGaudio, N. L., Uygur, B., Millet, A., Khan, A., Unlu, G., Xiao, M., Timson, R. C., Li, C., Ozcan, K., Smith, K. W., Martins Nascentes Melo, L., Allies, G., Basturk, O., Sickmann, A., Bayraktar, E. C., Possemato, R., Tasdogan, A., Birsoy, K.
(2025) Mitochondrial Glutathione Import Enables Breast Cancer Metastasis via Integrated Stress Response Signaling. Cancer Discovery. 15 (12), 2437–2449.
The Federal Ministry of Research, Technology and Space (Bundesministerium für Forschung, Technologie und Raumfahrt, BMFTR) is funding the MSCoreSys-associated junior research group Spatial Metabolomics under the funding number 161L0271.
