In a landmark study published in Nature, scientists from the Institut Curie have discovered a new approach to halting acute inflammation and sepsis, potentially saving millions of lives annually.
Their novel molecule, supformin, derived from the anti-diabetes drug metformin, can bind copper and prevent inflammatory processes identical to those in cancer dissemination.
A Metal-Driven Approach to Cancer and Inflammation
The project originated during the early days of the COVID-19 pandemic, with a focus on investigating cell state transitions influenced by the metal iron. This process, mediated by a protein called CD44, is present in activated immune cells and changes metabolic and epigenetic signatures of cancer cells.
With inflammation leading to septic shock identified as the leading cause of death in COVID-19 patients, researchers sought to understand these underlying processes in both inflammation and cancer. Screening for metal chelators, the team discovered a commonality in the biological processes of both conditions, leading to the development of a promising therapeutic agent: supformin.
How Supformin Stops Inflammation and Cancer Metastasis
When studying metal homeostasis in immune cells and cancer cells, researchers observed that inflammatory cells and aggressive cancer cells contained elevated levels of copper. This copper, carried into cells by the protein CD44, accumulates in mitochondria, crucial organelles responsible for energy production.
Here, copper catalyzes the interconversion of the key enzymatic co-substrates NAD(H). Researchers designed supformin to block this reaction by binding with copper. This interaction leads to changes in metabolite levels, triggering alterations in how genes are expressed, referred to as epigenetic changes.
Animal testing confirmed this process, showing that supformin could successfully prevent septic shock in mice. This breakthrough suggests that copper could be a key target in inflammation and cancer metastasis, opening a new avenue for therapeutic interventions.
Implications and Future Steps
This work reshapes our understanding of inflammation and metastasis formation in cancer, suggesting new therapeutic strategies. The identification of copper as a critical factor in these cellular processes, along with the successful application of supformin in animal models, could pave the way for the development of new medications for a broad range of conditions, including septic shock and cancer.
Further scientific work is needed to investigate whether this mechanism is universal in all cancer types and whether it could be exploited in other inflammatory settings, including chronic and acute inflammation. Supformin's effectiveness in human clinical trials is also yet to be determined. However, these initial findings provide a promising basis for future research.
The study also underscores the importance of metals in biological processes. Once seen merely as cofactors, metals like iron and copper should now be considered key cellular players, significantly impacting biology and the physical world alike.
The work is only the beginning, with many questions still to be answered. Supformin will have to be developed into an actual drug for the treatment of septic shock or the prevention of metastases formation. Further, the role of metals in other biological processes that underpin changes in cell states, such as development or erythropoiesis, remains to be explored.
Reference: Solier, S., Müller, S., Cañeque, T. et al. A druggable copper-signalling pathway that drives inflammation. Nature 617, 386–394 (2023). https://doi.org/10.1038/s41586-023-06017-4
