Authors: Campmans, XJ1, Van den Heuvel, M2, Sonke, GS3,4, Buiting, HM3,4,5 Amsterdam UMC, Department of Global Health, Amsterdam, the Netherlands Radboud UMC…
Septic shock and metastases: finding the culprits
Authors: Sebastian Müller, Stéphanie Solier and Raphaël Rodriguez
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; work that was published recently in Nature1.
The researchers found that cells responsible for metastasis formation or immune cells implicated in inflammation and sceptic shock have increased amounts of copper, which is responsible for changes in cell plasticity. Interestingly, copper is taken up into cells via a protein called CD44 and hyaluronic acid, also known to be an ingredient in many beauty products. There was already proof of metal uptake by CD44 in cancer cells by the research team, published previously in the journal Nature Chemistry2. CD44 is a protein that has been widely studied for decades and found in many cell types, including cells of the immune system, cancer cells, cells involved in wound healing, progenitor cells of red blood cells and many more. The scientists showed that copper taken up by CD44 accumulates in mitochondria of the cells, which are organelles responsible for energy production.
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.
Furthermore, 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 of septic shock.
But that was not all. The study also showed that these fundamental processes underlying inflammation are also found in cancer, more specifically in molecular events that can trigger metastasis formation! Thus, this approach could potentially be adopted to fight metastasis. Since more than 11 million people die of septic shock in the world per year and 90% of cancer deaths are due to metastases, there is now big hope that this can be developed into new medications, which could help many patients on a global scale.
Overall, this study now shows great promise, both on a molecular fundamental research level and potential clinical applications. It also poses the question of how much copper is good for us?
Illustration: model of the study.
The researchers Raphaël Rodriguez, Stéphanie Solier and Sebastian Müller. Image credit: Beloncle Frank/Institut Curie.
1) S. Solier#, S. Müller#, T. Cañeque#, A. Versini#, L. Baron, F. Sindikubwabo, A. Mansart, G. D. Pantoș, V. Gandon4, D. Guillemot, P. Gestraud, E. Girard, N. Servant, Q. Bardin, A. Sansoni, C. Pierini, P. Hoest, A. Zarubica, B. Malissen, N. S. De Silva, N. Manel, A. Puisieux, M. A. Dawson, S. Watson, G. Kroemer, D. Annane, R. Rodriguez. Discovery of a druggable copper signaling pathway that regulates inflammation. Nature, 2023, doi: 10.1038/s41586-023-06017-4.
2) S. Müller#, F. Sindikubwabo#, T. Cañeque, A. Lafon,A. Versini, T.-D. Wu, B. Lombard, D. Loew, A. Durand, C. Vallot,S. Baulande, N. Servant, R. Rodriguez. CD44 regulates epigenetic plasticity by mediating iron endocytosis. Nat. Chem., 2020,12, 929–938