Direct transdifferentiation of tumorigenic melanoma cells to non-tumorigenic neuron-like cells

Melanoma is an aggressive skin cancer and is highly lethal at advanced stages despite the availability of a variety of established therapeutic options due to the high tumorigenicity and metastatic capacity of melanoma cells. However, there is evidence that changing the lineage of cancer cells leads to a drastic reduction of their tumorigenic potential. Different approaches have been developed to change the phenotype of a cell from one lineage to another, a process called transdifferentiation. In this study, we investigated whether melanoma cells can be transdifferentiated into neurons and how that affects their properties and characteristics. For this reason, we ectopically overexpressed the neuron-specific transcription factors Ascl1, Brn2, Myt1L and NeuroD1 in melanoma cells. We could show that melanoma cells could be transdifferentiated into neuron-like cells that expressed neuronal markers and showed a neuron-like morphology. RNA sequencing and DNA methylation assay were used to further reveal the underlying mechanism. Moreover, the transdifferentiated cells had a significantly reduced tumorigenic and metastatic potential and were more sensitive to radiotherapy compared with their parental counterparts. We conclude that transdifferentiation of cancer cells into terminally differentiated cells could represent a new therapeutic alternative for the treatment of malignant melanoma.