A new way to target sepsis and metastases via a common molecular target

May 17, 2023 (Nanowerk Spotlight) Cells possess an innate ability to rapidly adapt to environmental chemical and physical stimuli. Although genetic mutations can elicit changes in cellular properties, a more immediate response is often driven by non-genetic mechanisms. This cellular agility, otherwise known as cell plasticity, plays a crucial role in the orchestration of fundamental biological processes, both in health and disease states. Consider, for instance, the dynamic nature of tumor cells. These cells can transition from a state of heightened proliferation to one of increased invasiveness, thereby facilitating the spread of cancer, or metastasis. Similarly, during inflammatory episodes, immune cells undergo a transformation, becoming active agents in the execution of an inflammatory response and the subsequent promotion of tissue repair. However, when this inflammatory response spirals out of control, it can precipitate tissue damage and even culminate in a life-threatening condition known as septic shock. A research team based at the Institut Curie in Paris has recently unveiled a new molecular actor in these processes: copper. Their findings, published in the journal Nature (“A druggable copper-signalling pathway that drives inflammation”) reveal that the fundamental processes driven by copper are consistent across both inflammation and cancer metastasis. Given the global health burden of these conditions — with more than 11 million annual fatalities from septic shock and 90% of cancer-related deaths attributable to metastases — the discovery of copper’s role could be a significant breakthrough. This newfound understanding of the influence of copper on cellular plasticity may pave the way for innovative therapeutic strategies in the future.

Inflammation caused by copper can be stopped by supformin

By analyzing metal homeostasis in immune cells called macrophages and in cancer cells, the research team discovered that both inflammatory and aggressively cancerous cells exhibit heightened levels of copper. The scientists designed a new molecule based on metformin, which can block this reaction by binding copper. Interestingly, this finding harkens back to a study from 1929 that first unveiled metformin’s ability to bind copper, albeit forming a 2:1 complex with two metformin molecules. The newly engineered molecule, named supformin, incorporates two metformin units, thereby enhancing its copper complex formation capacity. Impressively, supformin displays an efficacy that is 5000 times greater than that of its metformin counterpart. Reaction vial with copper solution (left) und copper solution with Supformin (right). The complex of supformin and copper gives a typical pink coloring. (Image courtesy of the researchers) The new drug specifically targets mitochondria, the cellular powerhouses responsible for energy production. Here, copper serves as a catalyst in the interconversion of vital enzymatic co-substrates, NAD(H). Within the mitochondria, supformin binds this copper to inactivate these metabolic processes. NAD(H) usually fuels the Krebs cycle, the major energy providing pathway in cells. By blocking NAD(H) generation, supformin precipitates a reduction in key metabolites crucial for facilitating epigenetic changes. These are non-genetic modifications that alter the cell’s phenotype. This causes a less inflammatory state in immune cells and a less aggressive state in cancer cells. The therapeutic potential of supformin was evidenced in several mouse models of sepsis, where the administration of supformin remarkably improved the animals’ survival rate.

How does copper get into the cells?

In these processes underlying cell plasticity, copper is taken up by 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 Chemistry (“CD44 regulates epigenetic plasticity by mediating iron endocytosis”). 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.

What is the greater picture?

This work provides a mechanistic understanding of cellular state control, illustrating how modifications in energy metabolism can induce epigenetic changes that influence gene expression. Historically, metals have been somewhat understated in their cellular roles, often being regarded as mere cofactors. However, given that many metals are potent catalysts in the physical world, and considering that life has evolved within the constraints of this physical world, they should be rightfully acknowledged as essential cellular components. Our results concerning 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. Consequently, there is potential for the development of novel medications for an extensive range of conditions, including septic shock and various forms of 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. The promise of supformin as a therapeutic agent will now need to be validated through rigorous testing and potential drug development processes. Moreover, given that supformin, which is based on metformin, targets mitochondrial copper, this work also suggests a general mode of action of the widely-used drug metformin. This could provide an explanatory framework for the diverse phenotypes and effects associated with metformin use, as documented in previous literature. By Sebastian Müller, Ph.D., Institut Curie, CNRS, INSERM, PSL Research University, Paris, France