Metformin reveals a mitochondrial copper addiction of mesenchymal cancer cells

The clinically approved drug metformin has been shown to selectively kill persister cancer cells through mechanisms that are not fully understood. To provide further mechanistic insights, we developed a drug surrogate that phenocopies metformin and can be labeled in situ by means of click chemistry. Firstly, we found this molecule to be more potent than metformin in several cancer cell models. Secondly, this technology enabled us to provide visual evidence of mitochondrial targeting with this class of drugs. A combination of fluorescence microscopy and cyclic voltammetry indicated that metformin targets mitochondrial copper, inducing the production of reactive oxygen species in this organelle, mitochondrial dysfunction and apoptosis. Importantly, this study revealed that mitochondrial copper is required for the maintenance of a mesenchymal state of human cancer cells, and that metformin can block the epithelial-to-mesenchymal transition, a biological process that normally accounts for the genesis of persister cancer cells, through direct copper targeting.