A regulatory prrx1-snail1 switch controls melanoma development
- Autores: Francisco Manuel Cabello Torres
- Directores de la Tesis: Berta López Sánchez-Laorden (dir. tes.)
- Lectura: En la Universidad Miguel Hernández de Elche ( España ) en 2025
- Idioma: español
- Tribunal Calificador de la Tesis: Celia Jiménez Cervantes Frigols (presid.), Juan Galcerán Saéz (secret.), Andrés Joaquín López Contreras (voc.)
- Programa de doctorado: Programa de Doctorado en Neurociencias por la Universidad Miguel Hernández de Elche
- Materias:
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- Resumen
Cutaneous melanoma is a highly aggressive skin cancer characterized by phenotypic plasticity and intratumoural heterogeneity. While a role of epithelial-to-mesenchymal transition transcription factors (EMT-TFs) in melanoma progression has been proposed, their contribution to melanomagenesis remains poorly understood. This study investigates the contribution of the EMT-TFs Prrx1 and Snail 1 to melanoma development using genetically engineered mouse models and in vitro melanocyte assays. We show that Prrx1 and Snail1 are expressed in melanocytes during the anagen phase of the hair cycle and in early melanomas, but their expression diminishes as tumours progress. Conditional knockout of Prrx1 in melanocytes accelerates melanoma onset and increases tumour number, without affecting proliferation.
Mechanistically, Prrx1 loss leads to upregulation of Snail1, which enhances stem-like properties in melanocytes. In contrast, Snail1 depletion delays melanoma initiation, and combined loss of Prrx1 and Snail1 phenocopies the wild-type phenotype, supporting that the mechanism by which Prrx1 depletion promotes melanomagenesis is driven by Snail1. In vitro experiments indicate a unidirectional regulatory axis where Prrx1 attenuates Snail1 expression via the miR-15 family microRNAs. These findings suggest that Prrx1 acts as a tumour suppressor in melanoma and highlight a novel Prrx1 Snail1 axis that regulates early melanocytic transformation. These results refine our understanding of melanoma initiation and suggest that targeting transcriptional reprogramming could offer new avenues for early intervention.
