Back and forth between tumor initiation and tissue repair to dissect epidermal stem cell memory and plasticity

It is well established that wound healing and epithelial cancer share a large set of features including immune cell infiltration, extracellular matrix remodelling by fibroblasts, induction of cell plasticity, an epithelial-to-mesenchymal(-like) behaviour and enhanced cell motility. Moreover, squamous cell carcinomas and epidermal cells involved in skin repair share a chromatin conformation state and a gene expression program, if compared to homeostatic conditions. Recently, we and others highlighted an important new link between wound healing and tumour initiation in epithelia. We showed that  epidermal cells undergoing an inflammatory event, such as an injury, acquire an epigenetic memory. This memory, similarly to trained immunity in immune cells, allows a more efficient response to a comparable future stimulus. Conversely, when exposed to carcinogenic stimuli, this wound memory exacerbated tumorigenesis. Overall, we showed that this cell adaptation to injury relies on spatially organised memory-dedicated progenitors, characterised by an actionable cell state that establishes an epigenetic field cancerization, predisposing cells to tumour onset. In this talk, I will discuss molecular and cellular features of this epithelial memory, including its sub-organ spatial distribution. I will also present our new genetic approach to identify epigenetic regulators of epidermal stem cell plasticity.