Epidermal tumour-resistant progenitors require SOX2-driven developmental reprogramming to drive tumorigenesis

The epidermal basal layer consists of two distinct progenitor populations contributing differentially to skin homeostasis or wound healing. However, their resilience to oncogenic insults is unknown. Here, we developed mouse models allowing lineage tracing and oncogene expression in both populations. Our findings support the existence of two long-lived and functionally distinct epidermal progenitors and define them as tumour-primed and tumour-resistant. The tumour-primed progenitors drive cutaneous squamous cell carcinoma (cSCC), within days from oncogenic expression resembling the rapid onset of BRAF-inhibitor-driven cSCC. The tumour-resistant progenitors transform gradually, requiring SOX2 activation. Once transformed, they share a transcriptomic profile revealing molecular hallmarks of epidermal transformation independently of the cell-of-origin or the oncogenic driving mutations. Importantly, SOX2 is expressed in a subset of cSCC patients hinting at its cell-of-origin. These highlight the need for an in-depth understanding of the cell-specific vulnerabilities that apply in each tissue to open new avenues for rational treatment.