The EMT Transcription Factor ZEB2 Promotes Proliferation of Primary and Metastatic Melanoma While Suppressing an Invasive, Mesenchymal-Like Phenotype
Niels Vandamme, Geertrui Denecker, Kenneth Bruneel, Gillian Blancke, Özden Akay, Joachim Taminau, Jordy De Coninck, Eva De Smedt, Nicolas Skrypek, Wouter Van Loocke, Jasper Wouters, David Nittner, Corinna Köhler, Douglas S. Darling, Phil F. Cheng, Marieke I.G. Raaijmakers, Mitchell P. Levesque, Udupi Girish Mallya, Máirín Rafferty, Balázs Bálint, William M. Gallagher, Liève Brochez, Danny Huylebroeck, Jody J. Haigh, Vanessa Andries, Florian Rambow, Pieter Van Vlierberghe, Steven Goossens, Joost J. van den Oord, Jean‐Christophe Marine, Geert Berx
Abstract
Abstract Epithelial-to-mesenchymal transition (EMT)-inducing transcription factors (TF) are well known for their ability to induce mesenchymal states associated with increased migratory and invasive properties. Unexpectedly, nuclear expression of the EMT-TF ZEB2 in human primary melanoma has been shown to correlate with reduced invasion. We report here that ZEB2 is required for outgrowth for primary melanomas and metastases at secondary sites. Ablation of Zeb2 hampered outgrowth of primary melanomas in vivo, whereas ectopic expression enhanced proliferation and growth at both primary and secondary sites. Gain of Zeb2 expression in pulmonary-residing melanoma cells promoted the development of macroscopic lesions. In vivo fate mapping made clear that melanoma cells undergo a conversion in state where ZEB2 expression is replaced by ZEB1 expression associated with gain of an invasive phenotype. These findings suggest that reversible switching of the ZEB2/ZEB1 ratio enhances melanoma metastatic dissemination. Significance: ZEB2 function exerts opposing behaviors in melanoma by promoting proliferation and expansion and conversely inhibiting invasiveness, which could be of future clinical relevance.