An interactive cellular ecosystem blocks epithelial transformation in naked mole-rat

Abstract

The mechanisms underlying cancer resistance in long-lived organisms are largely unexplored. Here, we report how naked mole-rats (Heterocephalus glaber) resist tumorigenesis when exposed to potent skin carcinogens. Single-cell transcriptional analysis of homeostatic full-thickness naked mole-rat skin revealed higher epidermal turn-over, a distinct composition of dermal extracellular matrix (ECM) and fewer resident T-cells, when compared to mouse and human. Carcinogenic treatment of skin generated the expected mutational landscape, but unlike in the mouse, failed to stimulate T-cells or generate tumours. Instead, naked mole-rat accelerated epidermal turnover to shed mutant cells. At the same time, the ECM was extensively remodelled via enhanced anti-inflammatory communication among fibroblasts and between fibroblasts and epidermal cells, creating a tumour-suppressive microenvironment. We demonstrate that, in contrast to mouse, naked mole-rat dermal fibroblasts lack intrinsic tumour promoting capabilities in vitro and in vivo. Our results demonstrate that the cellular ecosystem of naked mole-rat skin actively suppresses epithelial transformation.