Epidermal Snail expression drives skin cancer initiation and progression through enhanced cytoprotection, epidermal stem/progenitor cell expansion and enhanced metastatic potential

• Published in: Cell death and differentiation 2014-02, Vol.21 (2), p.310-320
• Main Authors: De Craene, B, Denecker, G, Vermassen, P, Taminau, J, Mauch, C, Derore, A, Jonkers, J, Fuchs, E, Berx, G
• Format: Article
• Language: English
• Subjects: 631/136/142; 631/67/1813; 631/67/322; 692/420/755; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Breast cancer; Cell Biology; Cell Cycle Analysis; Cell death; Cell Differentiation; Cell Proliferation; Disease Progression; Humans; Life Sciences; Medical prognosis; Metastasis; Mice; Mice, Transgenic; Molecular biology; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncology; Original Paper; Sebaceous Gland Neoplasms - genetics; Sebaceous Gland Neoplasms - pathology; Skin cancer; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Snail Family Transcription Factors; Stem Cells; Transcription factors; Transcription Factors - genetics; Transgenic animals; Tumors
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2013.148

Expression of the EMT-inducing transcription factor Snail is enhanced in different human cancers. To investigate the in vivo role of Snail during progression of epithelial cancer, we used a mouse model with skin-specific overexpression of Snail. Snail transgenic mice spontaneously developed distinct histological subtypes of skin cancer, such as basal cell carcinoma, squamous cell carcinoma and sebaceous gland carcinoma. Development of sebaceous gland carcinomas strongly correlated with the direct and complete repression of Blimp-1, a central regulator of sebocyte homeostasis. Snail expression in keratinocyte stem cells significantly promotes their proliferation associated with an activated FoxM1 gene expression signature, resulting in a larger pool of Mts24-marked progenitor cells. Furthermore, primary keratinocytes expressing Snail showed increased survival and strong resistance to genotoxic stress. Snail expression in a skin-specific p53-null background resulted in accelerated formation of spontaneous tumours and enhanced metastasis. Our data demonstrate that in vivo expression of Snail results in de novo epithelial carcinogenesis by allowing enhanced survival, expansion of the cancer stem cell pool with accumulated DNA damage, a block in terminal differentiation and increased proliferation rates of tumour-initiating cells.