Il ricordo di una lesione in aree integre rappresenta una cancerizzazione del campo epigenetico

Abstract

Epithelial cells that participated in a wound repair elicit a more efficient response to future injuries, that is believed to be locally restricted. Here we show that cell adaptation resulting from a localised tissue damage has a wide spatial impact at a scale not previously appreciated. Through cell population-specific genetical labelling and single cell transcriptomics, we demonstrate that specific stem cells, distant from the original injury, originate long-lasting wound memory progenitors. Notably these distal memory cells have not taken part in the first healing, but become intrinsically pre-activated through transcriptional priming. This cell state, maintained at chromatin and transcriptional level, leads to an enhanced wound repair that is partially recapitulated through epigenetic perturbation. Indeed, the observed reduction of the repressive histone mark H2AK119Ub is functional for the establishment of the distal memory. Moreover, while distal memory has a beneficial impact on future injuries, it also has long-term harmful consequences, exacerbating tumorigenesis. Overall, we show that sub-organ scale adaptation to injury relies on spatially organised memory-dedicated progenitors, characterised by an actionable cell state that establishes an epigenetic field cancerization and predisposes to tumour onset.