Contribution of the epithelial-to-mesenchymal transition transcription factor PRRX1 to melanoma plasticity and progression

Abstract

Melanoma is a very aggressive skin cancer, known for its high degree of plasticity and heterogeneity that confers high metastatic capabilities and resistance to therapies. Increasing evidences indicate that melanoma progression is not only regulated by mutation-driven mechanisms but also by non-genetic mechanisms that play an important role in melanoma phenotypic plasticity. The reactivation of the expression of neural crest genes in melanoma is associated to progression and resistance to therapies. Among those, epithelial-to-mesenchymal transcription factors (EMT-TFs) have been proposed to regulate reversible switches between phenotypic states driving melanoma progression. However the role of Prrx 1, an important EMT inducer also expressed during neural crest development, has not been investigated in detail. We have found that Prrx1 is expressed in melanoma and that Prrx1 downregulation induces cell cycle retention and reduces cell proliferation and cancer stem-like properties in melanoma cells. We have also generated a clinically relevant melanoma mouse model that cannot reactivate Prrx 1 expression in melanocytes to address the contribution ofthis EMT-TF to melanoma initiation, progression and responses to therapies.