Reprogramming the reactivity of iron in cancer
CD44 is a transmembrane glycoprotein that is linked to various biological processes reliant on the epigenetic plasticity of cells, including development, inflammation, immune responses, wound healing and cancer progression. While thoroughly studied, functional regulatory roles of this so-called ‘cell surface marker’ remain elusive. We discovered that CD44 mediates endocytosis of iron interacting with hyaluronates in tumorigenic cell lines and primary cancer cells. We found that this glycan-mediated iron endocytosis mechanism is enhanced during epithelial-mesenchymal transition (EMT), unlike the canonical transferrin-dependent pathway. EMT is further characterized by molecular changes required for iron-catalyzed oxidative demethylation of the repressive histone mark H3K9me2 that governs the expression of mesenchymal genes. CD44 itself is transcriptionally regulated by nuclear iron, demonstrating a positive feedback loop, which is in contrast to the negative regulation of transferrin receptor by excess iron. Finally, we show that epigenetic plasticity can be altered by interfering with iron homeostasis with spatial and temporal resolution using small molecules. This comprehensive study reveals an alternative iron uptake mechanism that prevails in the mesenchymal state of mammalian cells, illuminating a central role of iron as a rate-limiting regulator of epigenetic plasticity.
Raphaël Rodriguez carried out his PhD studies under the supervision of Sir J. Baldwin at Oxford (UK), where he completed the total synthesis of complex natural products. He joined the University of Cambridge in 2005 as a Cancer Research UK Postdoctoral Fellow, working under the mentorship of Sir S. Balasubramanian and was promoted to Senior Research Associate in 2009. From 2009 to 2012, he trained as a cell biologist under the guidance of Prof. S. Jackson at the Gurdon Institute in Cambridge. His studies established a firm link between G-quadruplex DNA and genome instability in human cells. In 2012, he obtained the Habilitation to Direct Research and joined the CNRS as a Principal Investigator. He then moved to Institut Curie in 2015 and was promoted Director of Research in 2017. His team investigates the role of d-block metals in the regulation of cellular plasticity, the biological process that enables cells to acquire metastatic and drug resistance properties. Their recent discovery that mesenchymal cancer cells are addicted to iron prompted the design of a new generation of drugs with controlled cellular localization. These molecules are able to reprogram the reactivity of iron, to abolish cellular plasticity and to kill persister cancer cells. He has gained international recognition with key contributions in chemistry and biology that can impact on human medicine. He co-authored 70 articles, books and scientific commentaries. He is listed as a co-inventor on several patents and commercialized 3 biologically active small molecules. He was awarded a competitive ERC consolidator grant, has been elected Fellow of the Royal Society of Chemistry, was recently nominated Franco-British Young Leaders, is a recipient of the Tetrahedron Young Investigator Award in Bioorganic and Medicinal Chemistry and has recently received the Grand Prix de l'Institut de France Charles Defforey. He is the scientific co-founder of the biotech company SideROS.