How do cells respond quickly to chemical and physical stimuli from their environment? Although genetic mutations can cause changes to cell properties, non-genetic mechanisms can drive rapid adaptation This so-called cell plasticity is involved in fundamental biological processes in health and disease. Tumour cells can shift from a highly proliferative state to a more invasive state, and thus promote metastasis. During inflammation, immune cells can transform into cells that execute an inflammatory response and promote tissue repair. Uncontrolled inflammation that gets out of hand can lead tissue damage and ultimately septic shock. Our research group at Institut Curie/ Paris now found a new culprit of these processes on a molecular level: copper, in a study now published in Nature. Therefore, the fundamental copper-driven processes we uncovered are identical in inflammation and in cancer dissemination. Since more than 11 million people die of septic shock every year and 90% of cancer deaths are due to metastases, this holds great promise for new therapy.
Do metals control cell states in inflammation and cancer?
The work started at the onset of the COVID-19 pandemic. We had previously found that the metal iron regulates cell state transitions, by changing metabolic and so-called epigenetic signatures of cancer cells. This is mediated by a protein called CD44, also overexpressed in activated immune cells. With the pandemic, it became clear that inflammation leading to septic shock is the major cause of death in COVID-19 patients. We set out to investigate these underlying processes in inflammation and screened for metal chelators, which could stop these processes, both in cancer and in infectious diseases. This was the genesis of a project that ultimately found that underlying biological processes in inflammation and cancer are identical, with a new premise for therapeutic intervention using a novel molecule called supformin.
Inflammation caused by copper can be stopped by supformin
By analyzing metal homeostasis in immune cells such as macrophages and in cancer cells, we found that immune cells in the inflammatory state and aggressive cancer cells have increased levels of copper. This copper is internalized into cells by the protein CD44 and accumulates in organelles important for energy production, called mitochondria, where it catalyzes the interconversion of the key enzymatic co-substrates NAD(H). We designed a new molecule based on metformin, which can block this reaction by binding copper. This leads to changes in metabolite levels, which are in turn essential for changing how genes are expressed, so-called epigenetic changes. This process was confirmed in animals, where this new molecule can prevent septic shock in mice.
The key findings of the paper were:
- Activated cell states have increased copper content
- Copper drives inflammation and potentially cancer metastasis
- Copper catalyzes the oxidation of the key biomolecule NADH
- A new small molecule based on metformin can stop inflammation and cell changes in cancer
Preventing sepsis and metastasis formation in cancer
This work establishes copper as a mechanistic target in inflammation and shows that it can be targeted with a drug. We demonstrate that the fundamental underlying processes are identical in cancer during metastasis formation, giving these pathways a general nature. Given that supformin, which is based on metformin, targets mitochondrial copper, this work also suggests a general mode of action of the widely-distributed drug metformin, which would explain other phenotypes and effects observed with metformin in the literature. The findings that copper catalyzes the interconversion of NAD(H) is important as these metabolites are crucial in numerous cellular reactions, in particular in mitochondria where they fuel the Krebs cycle, the major energy providing pathway in cells. This work gives a mechanistic basis of how cell states are controlled, i.e., via changes in energy metabolism, leading to epigenetic changes controlling gene expression. Metals have often been considered as mere cofactors in cells. However, some of these metals are formidable catalysts in the physical world and since life has evolved around the limitations of the physical world they should rather be considered as key cellular players, an idea put forward by Prof. Raphaël Rodriguez. Our results on iron and copper put these metals into the limelight of biology.
These findings change our understanding of how inflammation and metastasis formation in cancer are regulated and provide a new way to therapeutically intervene. New medications could thus be developed for an array of indications, including septic shock and cancer. This work revolutionizes how we consider changes in gene expression, putting mitochondria into the picture as being the cell organelle controlling the way cells behave. It also provides an interesting evolutionary angle, as mitochondria are thought to be derived from bacteria in the endosymbiotic hypothesis. Are we who we are because of bacteria billions of years ago?
Supformin has been successfully tested in animal models, but results in human clinical trials need to be conducted now. This process has already been initiated but still needs time and effort to come to fruition. This mechanism was investigated in immune cells and some models of cancer. Is it ubiquitous in all cancers? Can it be exploited in all inflammatory settings, including chronic and acute inflammation? This is not clear yet and will require further scientific work and rigorous clinical testing.
Where will this work lead in the future?
Supformin will now have to be developed into an actual drug to help people, be it for the treatment of septic shock or to prevent metastases formation. This area has great promise and will require painstaking and thorough scientific and clinical investigations. Is this pathway involved in other biological processes underpinning changes in cell states, such as development or erythropoiesis (red blood cell maturation)? This work will now open an entire new field to investigate the role of metals in cell plasticity.
Reference: Solier et al., A druggable copper-signalling pathway that drives inflammation, Nature, 2023, 617, 386–394, doi:10.1038/s41586-023-06017-4