Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling

Area of Science:

• Dermatology
• Molecular Biology
• Oncology

Background:

• The relationship between tissue changes and multifocal epithelial tumors remains unclear.
• Investigating the role of mesenchymal signaling in tumor initiation is crucial for understanding cancer development.

Purpose of the Study:

• To investigate whether loss of mesenchymal Notch/CSL signaling causes or results from tissue alterations preceding epithelial tumors.
• To explore the molecular mechanisms by which CSL-deficient fibroblasts promote tumor cell proliferation.

Main Methods:

• Utilizing genetically engineered mice with mesenchymal-specific deletion of CSL/RBP-Jκ.
• Analyzing dermal fibroblasts from knockout mice for changes in gene expression and growth factor secretion.
• Examining human skin samples adjacent to actinic keratosis lesions for Notch/CSL signaling alterations.
• Investigating the effects of UVA radiation on gene expression in skin samples.

Main Results:

• Mesenchymal-specific CSL/RBP-Jκ deletion in mice led to stromal atrophy and inflammation, preceding spontaneous multifocal keratinocyte tumors.
• CSL-deficient dermal fibroblasts exhibited upregulated c-Jun and c-Fos, increasing tumor cell proliferation via growth factors and inflammatory cytokines.
• Human skin adjacent to actinic keratosis showed decreased Notch/CSL signaling.
• UVA radiation induced similar gene expression changes, linking environmental factors to these molecular alterations.

Conclusions:

• Loss of mesenchymal Notch/CSL signaling is a potent trigger for epithelial tumors, initiating a cascade of tissue alterations.
• CSL-deficient fibroblasts create a tumor-promoting microenvironment through molecular signaling.
• These findings highlight the role of stromal signaling in skin cancer development and suggest potential therapeutic targets.