The role of a novel cross-talk between EpCAM and EGFR in the regulation of epithelial-to-mesenchymal transition (EMT) in head and neck carcinomas

Pan, Min (2019): The role of a novel cross-talk between EpCAM and EGFR in the regulation of epithelial-to-mesenchymal transition (EMT) in head and neck carcinomas. Dissertation, LMU München: Medizinische Fakultät

Abstract

Head and neck squamous cell carcinomas (HNSCCs) are characterized by remarkable molecular heterogeneity that leads to stark therapy resistance and dismal clinical outcome. Intratumoral heterogeneity provides the basis to foster epithelial-mesenchymal-transition (EMT), and thus firmly associates with tumor progression, treatment resistance, and metastasis formation. The present thesis addressed the expression and function of the major determinant of epithelial differentiation, EpCAM, and of the therapeutic target EGFR in clinical samples (n=180) and in vitro models of HNSCC. The observation that EGFRlow/EpCAMhigh HNSCC patients possess considerably improved survival raised important questions regarding the molecular mechanism for the observed discrepancies in clinical outcomes, which could be answered in depth in the present study. EGF/EGFR has dual capacity in cellular fate decision regarding proliferation and EMT, through shaping different ERK activation dynamics and, consequently, EGF/EGFR signaling modulates the expression of EMT-transcription factors (EMT-TFs) Slug, Snail, and Zeb1. Moreover, EpEX, the soluble ectodomain of EpCAM, was identified as a novel ligand of EGFR that activates pERK1/2 and pAKT, provokes EGFR-dependent proliferation, but impedes EGF-induced EMT. EpEX competitively rewires EGF/EGFR-ERK signaling and inhibits EMT-TF induction, leading to the inhibition of EGF-mediated EMT. The levels of pERK1/2 and Slug in clinical samples of HNSCC further reflected this mechanism, the high expression of which predicted poor clinical outcome. Therefore, the emerging crosstalk between EGFR and EpCAM, converging at the level of pERK, represents a promising target to improve patient-specific adjuvant treatment of HNSCCs.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: EGFR, EpCAM, EpEX, HNSCC, EMT, ERK
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 26. November 2019
• 1. Bericht­erstatter:in: Gires, Olivier