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SOX2 confers tumour permissiveness in a specific skin progenitor population
Centeno, P. P. Chester, C. Kanellos, G. Ford, C. A. Cammareri, P. Inman, G. J. Jamieson, T. Ridgway, R. A. Marais, R. Campbell, A. D.
Centeno, P. P.
Chester, C.
Kanellos, G.
Ford, C. A.
Cammareri, P.
Inman, G. J.
Jamieson, T.
Ridgway, R. A.
Marais, R.
Campbell, A. D.
Abstract
The continuous renewal of the skin relies on stem and progenitor cells, yet their differential susceptibility to oncogenic mutations in cutaneous squamous cell carcinoma (cSCC) remains unclear. Rapid cSCC develops in melanoma patients on BRAF inhibitors due to paradoxical MAPK activation. To model this in mice, we use two complementary approaches: HRASG12V with a BRAF inhibitor 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, showing a shared transformation process. However, SOX2 is uniquely upregulated in progenitor-derived tumours and is expressed in 20% of human cSCC, indicating it might mark tumours arising from committed progenitors. Here, we show that SOX2 overexpression, along with MAPK activation, in progenitors induces a stem-like state and renders this otherwise resistant population permissive to rapid transformation.
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Date
2026
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Article
Citation
Centeno PP, Chester C, Kanellos G, Ford CA, Cammareri P, Inman GJ, et al. SOX2 confers tumour permissiveness in a specific skin progenitor population. Nature Communications. 2026 JAN 8;17(1).