Chemical Control of Cell Plasticity

Summary

Cells can rapidly and reversibly adopt distinct states and this independently of genetic alterations, a biological mechanism commonly referred to as ‘cell plasticity’. CD44 is a plasma membrane glycoprotein associated with development, immune cell activation as well as tumorigenesis. Although often described as a cell-surface marker, the biological function of CD44 has remained elusive for half a century. We discovered that CD44 mediates the uptake of metals including copper and iron bound to hyaluronates in cells from distinct tissues. This glycan-mediated metal endocytosis mechanism is enhanced during immune cell activation and in cancer cells undergoing epithelial–mesenchymal transitions. We found that copper(II) catalyzes a previously uncharted chemical reaction in mitochondria required for the production of key metabolites. In contrast, iron is required in the nucleus to promote the activity of specific demethylases. Together, these metals orchestrate metabolic and epigenetic programming of cell plasticity, establishing CD44 as a regulator of cell state transition. We developed new classes of small molecules that selectively interfere with these metal-catalyzed chemical processes in cells. Supformin specifically targets mitochondrial copper(II), thereby antagonizing macrophage activation in several pre-clinical models of acute inflammation and cancer. This established a key concept in biology whereby pharmacological control of cell plasticity confers therapeutic benefits. This also suggest a competition for metal uptake by immune and cancer cells that may enable tumor progression. These findings illuminate a universal metal uptake mechanism and the critical role of metals as master regulators of cell plasticity, paving the way towards the development of next generation therapeutics.

Biography

Raphaël Rodriguez, PhD, FRSC, is a Research Director at the CNRS and a Senior Principal Investigator at Institut Curie where he holds the Marie Curie Chair of Chemical Biology. He acquired the knowledge of chemistry and biology under the mentorships of Sir J. E. Baldwin (Oxford, 2004), Sir S. Balasubramanian (Cambridge, 2005) and Sir S. P. Jackson (Cambridge, 2009). He established his lab at Institut Curie (Paris, 2015), where he investigates the molecular bases of cancer metastasis. There, Rodriguez discovered the central role of metals as regulators of cell identity. He is a Fellow of the Royal Society of Chemistry (FRSC) and received a Knighthood of the National Order of Merit from Jean-Marie Lehn on behalf of Emmanuel Macron. He has received a few accolades for his scientific contributions including the Liliane Bettencourt Prize for Life Sciences, Klaus Grohe Prize, Tetrahedron Young Investigator Award, Antoine Lacassagne Prize (Collège de France) and Charles Defforey Prize (Institut de France).