SOX2 confers tumour permissiveness in a specific skin progenitor population.

The skin’s continuous renewal relies on stem and progenitor cells, yet their differential susceptibility to oncogenic mutations in cutaneous squamous cell carcinoma (cSCC) remains poorly understood. Rapid cSCC development occurs in melanoma patients treated with BRAF inhibitors, driven by paradoxical MAPK activation. To model this in mice, we use two complementary approaches: HRASG12V with BRAFi to mimic paradoxical MAPK activation, and BRAFV600E, which drives MAPK hyperactivation without further treatment. We target these mutations to the interfollicular stem and differentiation-committed progenitors of the basal epidermis. While stem cells rapidly form tumours, progenitors exhibit long-latency resistance despite retaining mutations and repopulating the basal layer. Ultimately, both populations produce similar tumours, revealing a shared transformation programme. However, SOX2 is uniquely upregulated in tumours from the progenitor population. SOX2 is expressed in 20% of human cSCC, suggesting that it could mark tumours originating from committed progenitors. Here, we show that SOX2 overexpression in progenitors induces a stem-like state and renders this otherwise resistant population permissive to transformation.