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Pan, M.* ; Schinke, H.* ; Luxenburger, E.* ; Kranz, G.* ; Shakhtour, J.* ; Libl, D.* ; Huang, Y.* ; Gaber, A.* ; Pavšič, M.* ; Lenarčič, B.* ; Kitz, J.* ; Jakob, M.* ; Schwenk-Zieger, S.* ; Canis, M.* ; Hess-Rieger, J. ; Unger, K. ; Baumeister, P. ; Gires, O.

EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers.

PLoS Biol. 16:e2006624 (2018)
Verlagsversion Forschungsdaten DOI
Open Access Gold
Creative Commons Lizenzvertrag
Head and neck squamous cell carcinomas (HNSCCs) are characterized by outstanding molecular heterogeneity that results in severe therapy resistance and poor clinical outcome. Inter- and intratumoral heterogeneity in epithelial-mesenchymal transition (EMT) was recently revealed as a major parameter of poor clinical outcome. Here, we addressed the expression and function of the therapeutic target epidermal growth factor receptor (EGFR) and of the major determinant of epithelial differentiation epithelial cell adhesion molecule (EpCAM) in clinical samples and in vitro models of HNSCCs. We describe improved survival of EGFRlow/EpCAMhighHNSCC patients (n = 180) and provide a molecular basis for the observed disparities in clinical outcome. EGF/EGFR have concentration-dependent dual capacities as inducers of proliferation and EMT through differential activation of the central molecular switch phosphorylated extracellular signal–regulated kinase 1/2 (pERK1/2) and EMT transcription factors (EMT-TFs) Snail, zinc finger E-box-binding homeobox 1 (Zeb1), and Slug. Furthermore, soluble ectodomain of EpCAM (EpEX) was identified as a ligand of EGFR that activates pERK1/2 and phosphorylated AKT (pAKT) and induces EGFR-dependent proliferation but represses EGF-mediated EMT, Snail, Zeb1, and Slug activation and cell migration. EMT repression by EpEX is realized through competitive modulation of pERK1/2 activation strength and inhibition of EMT-TFs, which is reflected in levels of pERK1/2 and its target Slug in clinical samples. Accordingly, high expression of pERK1/2 and/or Slug predicted poor outcome of HNSCCs. Hence, EpEX is a ligand of EGFR that induces proliferation but counteracts EMT mediated by the EGF/EGFR/pERK1/2 axis. Therefore, the emerging EGFR/EpCAM molecular cross talk represents a promising target to improve patient-tailored adjuvant treatment of HNSCCs.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Squamous-cell Carcinoma; Pd-0325901 Overcomes Resistance; Current Treatment Options; Breast-cancer; Pancreatic-cancer; Predicts Poor; Stem-cells; Oropharyngeal Carcinoma; Prognostic-significance; Tonsillar Carcinomas
ISSN (print) / ISBN 1544-9173
e-ISSN 1545-7885
Zeitschrift PLoS Biology
Quellenangaben Band: 16, Heft: 9, Seiten: , Artikelnummer: e2006624 Supplement: ,
Verlag Public Library of Science (PLoS)
Verlagsort 1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
Begutachtungsstatus Peer reviewed
Institut(e) CCG Personalized Radiotherapy in Head and Neck Cancer (KKG-KRT)
Research Unit Radiation Cytogenetics (ZYTO)