New Insights into the Phenotype Switching of Melanoma

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.

Keywords: dedifferentiation; melanoma; non-mutational reprogramming; phenotype switching; plasticity; resistance; targeted therapies.

Figure 1

Different transcriptional programs have been defined throughout the years. Starting from an initial dual classification recognizing only a more differentiated “proliferative” state and a less differentiated “invasive” state, the range of transcriptional programs is nowadays increasing, following a progressive model of plasticity. So far, six transcriptional programs have been described: hyperdifferentiated cells, melanocytic proliferation cells, transitory-intermediate migrating cells, therapy-induced starved-like melanoma cells, NCSC-like cells, and MITF-negative undifferentiated cells. In the figure, all different transcriptional states are reported with their respective markers (created with BioRender.com).

Figure 2

Summary of the different aspects of melanoma plasticity: origin of plasticity, transcriptional programs, advantages of plasticity, and new therapeutic strategies targeting plasticity (created with BioRender.com).