# SOX2 confers tumour permissiveness in a specific skin progenitor population

## TL;DR

This study shows that SOX2 overexpression makes skin progenitor cells more likely to develop cancer when exposed to certain mutations.

## Contribution

The study reveals that SOX2 overexpression in progenitor cells enables rapid tumor formation in a specific skin cell population.

## Key findings

- Stem cells rapidly form tumors, while progenitors are initially resistant despite carrying mutations.
- SOX2 is uniquely upregulated in progenitor-derived tumors and is present in 20% of human cSCC.
- SOX2 overexpression in progenitors induces a stem-like state and makes them permissive to transformation.

## 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.

The oncogenic potential of interfollicular stem and progenitor cells in cutaneous squamous cell carcinoma (cSCC) remains poorly understood. Here, the authors modelled rapidly growing cSCC driven by the hyperactivation of the MAPK signalling pathway in mice and showed that SOX2 overexpression renders progenitor cells prone to transformation.