RESUMEN

Melanomas are known to exhibit phenotypic plasticity. However, the role cellular plasticity plays in melanoma tumor progression and drug resistance is not fully understood. Here, we used reprogramming of melanocytes and melanoma cells to induced pluripotent stem cell (iPSCs) to investigate the relationship between cellular plasticity and melanoma progression and mitogen-activated protein kinase (MAPK) inhibitor resistance. We found that melanocyte reprogramming is prevented by the expression of oncogenic BRAF, and in melanoma cells harboring oncogenic BRAF and sensitive to MAPK inhibitors, reprogramming can be restored by inhibition of the activated oncogenic pathway. Our data also suggest that melanoma tumor progression acts as a barrier to reprogramming. Under conditions that promote melanocytic differentiation of fibroblast- and melanocyte-derived iPSCs, melanoma-derived iPSCs exhibited neural cell-like dysplasia and increased MAPK inhibitor resistance. These data suggest that iPSC-like reprogramming and drug resistance of differentiated cells can serve as a model to understand melanoma cell plasticity-dependent mechanisms in recurrence of aggressive drug-resistant melanoma.

Asunto(s)

Células Madre Pluripotentes Inducidas/metabolismo , Melanoma/metabolismo , Melanoma/patología , Células Madre Neoplásicas/metabolismo , Fenotipo , Biomarcadores de Tumor , Diferenciación Celular , Línea Celular Tumoral , Plasticidad de la Célula , Reprogramación Celular/efectos de los fármacos , Reprogramación Celular/genética , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/patología , Melanocitos/metabolismo , Melanoma/genética , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Mutación , Células Madre Neoplásicas/patología , Inhibidores de Proteínas Quinasas/farmacología