New Insights into the Phenotype Switching of Melanoma

Simple Summary Late-stage melanoma is one of the leading causes of death from skin cancers, as it frequently acquires resistance to standard therapies. Melanoma aggressiveness relies both on high intratumoral heterogeneity and on the capability of melanoma cells to switch among different differentiation phenotypes. Recently, melanoma plasticity has indeed been pinpointed as a main cause of resistance to standard therapies. Melanoma takes advantage of extrinsic reprogramming, a common feature exploited also by melanocytes, to promote tumor progression. Unfortunately, extrinsic factors and molecular mechanisms driving phenotype switching upon treatment are yet to be thoroughly characterized. The aim of this review is to support this field of research by providing brand-new insights into melanoma plasticity. Starting from the origin of phenotype switching, we will report up-to-date molecular players and extrinsic factors determining different transcriptional programs. Finally, the latest therapeutic strategies to tackle this mechanism of resistance will be discussed. Abstract Melanoma is considered one of the deadliest skin cancers, partly because of acquired resistance to standard therapies. The most recognized driver of resistance relies on acquired melanoma cell plasticity, or the ability to dynamically switch among differentiation phenotypes. This confers the tumor noticeable advantages. During the last year, two new features have been included in the hallmarks of cancer, namely “Unlocking phenotypic plasticity” and “Non-mutational epigenetic reprogramming”. Such are inextricably intertwined as, most of the time, plasticity is not discernable at the genetic level, as it rather consists of epigenetic reprogramming heavily influenced by external factors. By analyzing current literature, this review provides reasoning about the origin of plasticity and clarifies whether such features already exist among tumors or are acquired by selection. Moreover, markers of plasticity, molecular effectors, and related tumor advantages in melanoma will be explored. Ultimately, as this new branch of tumor biology opened a wide landscape of therapeutic possibilities, in the final paragraph of this review, we will focus on newly characterized drugs targeting melanoma plasticity.