During the metastasis process, cancer cells encounter a metabolic environment that is completely different from that of the primary tissue.
Successful colonization of distant organs requires adaptation to these new nutritional and stress conditions.
For instance, colon cancer cells absorb ATP in the form of phosphocreatine from the extracellular space to overcome the energy limitation of the liver.
The nutrient supply of the transfer microenvironment also plays a crucial role.
The limitation of asparagine can affect the epithelial-mesenchymal transition (EMT) of breast cancer.
Other metabolites, such as lactic acid, pyruvate, glutamine and serine, support different stages of the transfer cascade reaction.
Although many studies have focused on the nutritional availability of the metastatic microenvironment, little is known about how subcellular metabolism promotes this process.
In organelles, mitochondria are responsible for generating energy and providing the metabolites necessary for the occurrence and development of tumors.
Mitochondria are also involved in the production of reactive oxygen species (ROS) and signaling molecules, which regulate the behavior of cancer cells.
Recent studies have linked mitochondrial activity to metastasis.
Enhanced activity of the electron transport chain (ETC) driven by PGC1-α expression or superoxide formation is associated with the metastasis of breast cancer and renal cancer.
In pancreatic cancer, the absorption of mitochondrial calcium ions may promote metastasis by enhancing resistance to metabolic stress.
In some cases, transfer potential is associated with weakened mitochondrial function.
Despite these findings, the specific contributions of individual mitochondrial metabolites to different transfer stages remain poorly understood.
The cellular and metabolic heterogeneity of the metastatic microenvironment further exacerbates this complexity.
Recently Professor K. van Birsoy from the metabolic Regulation and Genetics Laboratory at Rockefeller University in the United States published an article in the journal Cancer Discovery: Mitochondrial Glutathione import enables breast cancer metastasis via integrated stress response signaling.
This study indicates that mitochondrial glutathione (GSH) input through SLC25A39 is crucial for the early metastatic colonization of breast cancer, as it links metabolic adaptation with stress response signals.
Targeting this pathway may reveal the vulnerability of metastasis-specific therapy without affecting the growth of the primary tumor.
Cancer cells need to undergo extensive metabolic adaptations to metastasize to distant organs, but the metabolites necessary for successful colonization remain unclear.
To clarify the metabolic profile of metastatic cancer cells at the organelle and cellular levels, the research team analyzed the mitochondrial metabolites of primary tumors and their metastatic tumors using the mitochondrial pull-down method.
This analysis revealed the different metabolic programs between primary tumors and metastatic tumors.
The research results show that during the lung metastasis of breast cancer cells, the accumulation of mitochondrial glutathione (GSH) is driven by the increased expression of the mitochondrial GSH transporter SLC25A39.
Deletion or blockade of SLC25A39 can impair metastatic colonization in gene screening, cell line models and patient-derived xenografts, but does not affect the growth of primary tumors.
On the contrary, increasing mitochondrial glutathione accelerates metastatic colonization, suggesting that mitochondrial glutathione plays a limiting role in metastasis.
The input of mitochondrial glutathione is a unique and essential process in the early colonization process, and its function is independent of its typical antioxidant effect.
CRISPR activation screening revealed that the stress-induced transcription factor ATF4 is a bypass mechanism that can restore the metastatic potential of SLC25A39-deficient cells.
Mechanologically speaking, SLC25A39 is essential for the optimal activation of ATF4 under transfer and hypoxia conditions, thereby linking the availability of mitochondrial glutathione to integrated stress response signals.
These findings suggest that mitochondrial glutathione is a necessary and restrictive metabolite for metastasis progression.
In conclusion, this study indicates that mitochondrial glutathione (GSH) input through SLC25A39 is crucial for the early metastatic colonization of breast cancer, as it links metabolic adaptation with stress response signals.
Targeting this pathway may reveal the vulnerability of metastasis-specific therapy without affecting the growth of the primary tumor.
The original link: https://doi.org/10.1158/2159-8290.CD-24-1556
