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

Area of Science:

• Oncology
• Molecular Biology
• Dermatology

Background:

• The epithelial-mesenchymal transition (EMT)-inducing transcription factor Snail is upregulated in various human cancers.
• Understanding Snail's in vivo role is crucial for epithelial cancer progression research.

Purpose of the Study:

• To investigate the in vivo function of Snail in the development and progression of epithelial skin cancer.
• To elucidate the mechanisms by which Snail contributes to skin carcinogenesis.

Main Methods:

• Generation of a mouse model with skin-specific Snail overexpression.
• Analysis of tumor histology and molecular markers in Snail transgenic mice.
• Assessment of keratinocyte proliferation, survival, and response to genotoxic stress.
• Evaluation of tumor formation and metastasis in a p53-null background.

Main Results:

• Snail overexpression induced spontaneous skin cancers, including basal cell carcinoma, squamous cell carcinoma, and sebaceous gland carcinoma.
• Sebaceous gland carcinoma development correlated with Snail-induced repression of Blimp-1.
• Snail promoted keratinocyte stem cell proliferation via FoxM1 activation, expanding progenitor cells.
• Snail expression enhanced keratinocyte survival and resistance to DNA damage.
• Snail accelerated tumor formation and metastasis in a p53-null background.

Conclusions:

• In vivo Snail expression drives de novo epithelial carcinogenesis.
• Snail facilitates cancer by enhancing cell survival, expanding the cancer stem cell pool, blocking differentiation, and increasing proliferation.
• Snail plays a significant role in tumor initiation and progression, including metastasis.