Pten loss in Lgr5⁺ hair follicle stem cells promotes SCC development

Accumulating data support that tissue stem cells give rise to cancer cells. Hair follicle stem cells (HFSCs) undergo cyclic quiescence and activation and may sever as the origin of cutaneous squamous cell carcinoma (SCC). Pten is a tumor suppressor gene that is frequently mutated in hereditary cancer syndromes such as Cowden disease, which is featured with papillomatosis in cutaneous tissues and hyperkeratosis in the acral region of the skin. Additionally, mice with keratinocyte-specific Pten deficiency (k5-Pten mice) show epidermal hyperplasia and spontaneous tumor formation. However, the impact of Pten mutation in HFSCs, such as in Lgr5⁺ HFSCs, on SCC formation is unclear. Methods: We established experiments with wildtype and Lgr5-CreER; Pten mice, and used DMBA/TPA two-stage skin carcinogenesis model to explore the effect of Pten loss in Lgr5⁺ HFSCs of 3 weeks old mice in skin carcinogenesis. In vitro experiments (cell culture and protein expression analysis) are employed to investigate molecular mechanisms involved. Results: Pten loss in Lgr5⁺ HFSCs promoted SCC formation, which was attenuated in TNF mice. Notably, β-catenin loss in Lgr5⁺ HFSCs decreased the formation of SCC. In addition, Pten loss in cultured epidermal stem cells upregulated the levels of both phospho-Akt and β-catenin. Conclusion: Pten loss in Lgr5⁺ cells induced Akt/β-catenin signaling, and SCCs can subsequently be raised as progeny from these primed Lgr5⁺ stem cells.