Melanoma is the most deadly form of skin cancer arising from melanocytes, endowed with unique features of cellular plasticity. During the first years of my PhD, we have been studying different aspects of the melanocytic spectrum ranging from melanocyte development, melanocyte stem cell homeostasis and melanoma progression. Epithelial-to-mesenchymal transition (EMT) is the process in which epithelial cells lose their epithelial characteristics and become migratory. Although melanocytes are not epithelial cells, we have shown that EMT-inducing transcription factors such as ZEB1 and ZEB2 play pivotal functions in the cellular plasticity of melanocytes and melanoma. Our findings have led to the hypothesis that melanoma cells cycle between a differentiated state with high levels of ZEB2 and an invasive cell state dictated by ZEB1, referred to as 'phenotype-switching'. The study of both physiological and pathological functions of ZEB1 and ZEB2 in the melanocytic lineage contributed significantly to the understanding how master regulators of EMT orchestrate the acquisition of high grade malignancy in melanoma. Recently, we have gained evidence that ZEB1 does not only contributes to cellular plasticity in established melanomas, it can also act as driver of melanoma development. This research project proposal is centered on melanocytic nevi or moles. Nevi are benign lesions, often harboring activated oncogenes such as BRAF and NRAS. Initially these oncogenes act mitogenically but these do not appear to initiate oncogenic transformation in situ as additional co-operating genetic insults are required. Benign nevi carrying BRAF or NRAS mutations display many features of oncogene-induced senescence (OIS). This anti-oncogenic fail-safe mechanism explains why most human nevi never progress to melanoma. The molecular mechanism underlying malignant transformation from nevus to melanoma is not fully understood. We have adopted unique mouse models that recapitulate how oncogene-induced senescence takes place in vivo and how it can be subverted to a malignant state. Preliminary experimental data indicate that forced expression of ZEB1 abrogates BRAFveooE_induced senescence in nevi and contributes to melanoma development. Therefore, the primary focus of this research project is to unravel how ZEB1 expression can be a driver of melanocyte transformation and melanoma initiation by identifying the key players that are mechanistically involved. In addition, ZEB1 expression will be analyzed in human nevus and melanoma specimens to investigate its clinical relevance in melanoma initiation.