DEATH-FATE

Cell death occurs as we speak in a continuous effort to maintain the structural and functional integrity of all living organisms. This is done by eliminating millions of cells every second. Cell death has highly diverse modes of execution (such as apoptosis, necroptosis, caspase-independent cell death or pyroptosis, for example) and a complex regulation by different molecular players. A fault in its regulatory network is unfortunately at the origin of many diseases: for instance, an excess of neuronal cell death could cause several neurodegenerative diseases, while blocking this process is sometimes a key pro-oncogenic trigger. The most well studied form of cell death is apoptosis. It relies mainly on two effectors: the mitochondria, a suicide capsule acting as a trigger when it undergoes permeabilisation and a class of cysteine proteases called caspases that precipitate apoptosis by cleaving hundreds of vital substrates. For many years cell death was studied as a silent event, which is merely the consequence of internal or external lethal stimuli such as DNA damage, death ligands or nutrient deprivation. Up to now, far too little attention has been paid to the influence of cell death on its microenvironment. In addition, cell death is still widely considered a black-or-white event: a cell can be either dead or alive, although evidence of vital caspase activation starts to emerge. In sharp contrast with the existing dogma, my team aims to study cell death from an integrative point of view: instead of a simple endpoint, we will study cell death as a powerful selection pressure that actively drives the emergence of novel phenotypic traits in its microenvironment. To test this hypothesis for which we already have promising preliminary data, we propose several interconnected approaches that focus on incorporating cell death into its milieu. The first aim is to study whether similarly to apoptosis, other types of cell death such as caspase-independent cell death could promote the proliferation of neighbouring cells in a paracrine manner. To this end, we will characterize in detail the para- and juxtacrine signalling between dying and living neighbouring cells using innovative in vitro approaches. Secondly, we set up a cellular model to trigger non-lethal caspase activation and evaluate in a cell-autonomous manner the emergence of new phenotypic traits in surviving cells, with emphasis on cell motility. Finally, we address whether cell death machinery could also impact on the function of stem cells, another critical component of the cell death microenvironment. The importance and originality of this project are that it explores cell death as a direct modulator of vital functions, ranging from proliferation, motility or stemness. I am confident this study will lead to major advances in our understanding of the molecular mechanisms allowing the dialogue between the living and the dead, while possibly offering promising therapeutic targets for neurological, developmental or immune diseases.