Chemical control of cell plasticity in cancer and inflammation

Cells can rapidly and reversibly adopt distinct states and this can occur 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 remains elusive. 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 transition. 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 validates 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. Structurally distinct classes of small molecule were developed to manipulate lysosomal iron providing control of cell fate with induction of or protection against ferroptosis . 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.