EGFR is involved in dermatofibrosarcoma protuberans progression to high grade sarcoma

Area of Science:

• Oncology
• Molecular Biology
• Dermatology

Background:

• Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue sarcoma with slow growth but potential for recurrence and transformation.
• The molecular drivers of DFSP transformation to higher-grade sarcoma (DFSP-T) are not fully understood.
• While COL1A1-PDGFB rearrangements are common in DFSP, they don't correlate with its evolutive potential.

Purpose of the Study:

• To investigate the role of Epidermal Growth Factor Receptor (EGFR) in the progression of DFSP to DFSP-T.
• To identify molecular pathways activated by EGFR during DFSP evolution.
• To explore potential therapeutic targets for advanced DFSP.

Main Methods:

• Laser-microdissection of DFSP center, infiltrative periphery, and DFSP-T areas from 22 patient samples.
• Analysis of EGFR protein and mRNA expression.
• Assessment of EGFR, KRAS, BRAF, NRAS mutations and copy-number variations.
• Evaluation of epithelial-mesenchymal transition factors (SNAIL, ZEB, TWIST).
• Proteome profiler phospho-kinase array to analyze EGFR downstream signaling pathways.

Main Results:

• EGFR expression (protein and mRNA) was detected in 13/22 patients and increased with tumor progression and local extension.
• No cancer-associated EGFR mutations or copy-number variations, nor KRAS, BRAF, NRAS mutations were found.
• SNAIL 1/2 expression paralleled EGFR expression, unlike ZEB1/2 or TWIST1/2.
• EGFR phosphorylation was detected in DFSP and DFSP-T samples.
• Positive correlations were found between EGFR phosphorylation and STAT5a/b (r=0.87) and TOR (r=0.95), but not ERK.

Conclusions:

• EGFR and SNAIL are implicated in DFSP progression to high-grade sarcoma.
• EGFR activation and signaling via TOR and STAT5a/b pathways are key events in DFSP evolution.
• Targeting EGFR signaling pathways may offer new therapeutic strategies for advanced DFSP.