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. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/14/2983/F1.large.jpg.

Highlights

  • Cutaneous melanoma is the most aggressive form of skin cancers and remains a major clinical challenge

  • The Tyr::NRASQ61K;TyrCreERT2;Trp53lox/lox mice have been intercrossed with mice carrying a conditional Zeb2 knockout allele (Zeb2fl/fl; refs. 10, 14)

  • In support of our findings, ZEB2 was instead recently identified as an “Achilles heel” of melanoma growth in a genome-wide RNAi-based loss-of-function screen aiming at establishing a “cancer dependency map” [26]

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Summary

Introduction

Cutaneous melanoma is the most aggressive form of skin cancers and remains a major clinical challenge. Oral Immunology and Infectious Diseases, and Center for Genetics and Molecular Medicine, University of Louisville, Louisville, Kentucky. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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