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: Faculty of Medicine |
Preview |
PDF
Pan_Min.pdf 120MB |
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.
Item Type: | Theses (Dissertation, LMU Munich) |
---|---|
Keywords: | EGFR, EpCAM, EpEX, HNSCC, EMT, ERK |
Subjects: | 600 Technology, Medicine 600 Technology, Medicine > 610 Medical sciences and medicine |
Faculties: | Faculty of Medicine |
Language: | English |
Date of oral examination: | 26. November 2019 |
1. Referee: | Gires, Olivier |
MD5 Checksum of the PDF-file: | d39a11d23178d62f98452f567a82ab1d |
Signature of the printed copy: | 0700/UMD 17899 |
ID Code: | 25221 |
Deposited On: | 12. Dec 2019 09:58 |
Last Modified: | 23. Oct 2020 14:45 |