Epidermal tumour-resistant progenitors require SOX2-driven developmental reprogramming to drive tumorigenesis
The skin undergoes continuous renewal, relying on stem and progenitor cells to maintain its barrier function. Over time, multiple oncogenic and tumour suppressor events accumulate. How the skin tolerates these mutations in different populations and how cutaneous squamous cell carcinoma (cSCC) emerges from mutant clones is poorly understood. Rapid cSCC development can ensue in melanoma patients treated with BRAF inhibitors (BRAFi) through paradoxical activation of RAF signalling. To model this in mice, we induced MAPK hyperactivation in two epidermal basal populations: stem-cell-like (K14/K5+) and differentiation-committed (IVL+) cells. Remarkably rapid tumorigenesis ensued from the K14/K5+ basal population defining them as a tumour primed. In contrast, despite mutations being retained and populating the skin, IVL+ cells exhibited tumour resistance with long latency. Nevertheless, both populations can act as cSCC cells of origin. Once transformed, they share histological and transcriptomic hallmarks of epidermal transformation independently of the cell-of-origin or the oncogenic driving mutations. Critically, the pioneer factor SOX2 was uniquely upregulated in tumours arising from the resistant population and was both necessary and sufficient for their transformation. Notably, SOX2 bestow an embryonic profile to human keratinocytes and is expressed in [~]20% of human cSCC, suggesting that it could mark tumours originating from committed progenitors. HighlightsO_LIParadoxical MAPK signalling activation is a tumour promoter in cSCC C_LIO_LIK14/K5+ represent a tumour-primed population and IVL+ represents a tumour-resistant population, but both can initiate skin cancer C_LIO_LIOncogene-expressing tumour-resistant population takes over the entire skin epidermis but preserves homeostasis C_LIO_LISOX2 is sufficient to initiate cSCC from the tumour-resistant population by preventing delamination and differentiation and promoting stemness C_LI