549 Targeting human skin SCC growth and metastasis at different stages of progression

Squamous cell carcinoma (SCC) is the second most frequent skin cancer in humans. Most of SCCs are treated by surgical excision, but 5-8% of patients develop recurrent tumors that show an aggressive growth and enhanced metastasis. Advanced and high-risk skin SCCs are treated with chemotherapy and radiotherapy with poor clinical benefits. To determine mechanisms regulating SCC growth and metastasis, we generated patient-derived xenografts by engrafting patient samples of well-differentiated (WD-SCCs) and poorly-differentiated SCCs (PD-SCCs) in immunodeficient mice. We found that PD-SCCs exhibit an expansion of CD44+ cancer stem cell population and a strong induction of the epithelial-to-mesenchymal transition program, correlating with an aggressive growth and enhanced metastasis. Autocrine activation of EGFR signaling promotes WD-SCC cell proliferation and Gefitinib treatment blocks WD-SCC growth. However, after EGFR inhibition, WD-SCC cell proliferation can be recovered by activation of FGFR signaling, suggesting that this signaling switch may be responsible of acquired resistance to EGFR inhibition. In contrast, PD-SCC cells show an attenuation of EGFR signaling and undergo the induction of FGFR1 and PDGFR signaling, being this last pathway responsible to promote tumor cell invasion and metastasis. These results indicate that regulatory mechanisms controlling SCC growth and metastasis change during progression, and suggest that pharmacological inhibition of both EGFR and FGFRs pathways may be a therapeutic strategy for treating WD-SCCs in order to avoid SCC recurrence.