New hopes to treat sepsis and metastases: A drug based on metformin binds copper

How can cells of the human body respond quickly to physical and chemical changes in their environment? Although genetic mutations can cause changes to the properties of a cell, non-genetic mechanisms can drive rapid adaptation, in a process broadly termed cell plasticity. Cell plasticity is involved in fundamental biological processes in health and disease. For example, tumour cells can shift from a highly proliferative state to a more invasive state, and thus promote cancer metastasis.

On the other hand, 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. A research group at Institut Curie in Paris now found a new culprit of these processes on a molecular level. This work was recently published in the scientific journal Nature.

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.

Further police work to investigate the fundamental processes have led to the findings that copper controls metabolism in these mitochondria, i.e. has direct effects on the energy production of the cell. This in turn changes levels of molecules called metabolites, which influence how genes are read in the cell. In particular levels of NAD(H) were affected, which are one of the most known and most important metabolites known in human cells. In short, these changes have an effect what the cell can do and look like and affect its function. The scientists developed a new small drug-like molecule, based on the anti-diabetes drug metformin, which can block these processes by binding and inactivating this copper. This then influences the energy production of the cell and ultimately its function. In the context of immune cells, the researchers could thus achieve less aggressive immune cells and dampen inflammation in mouse models. This new drug prototype could rescue mice from septic shock.

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?

: Fig.1: Supformin: typical pink color
when complexed with copper

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.

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

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