Abstract
Melanoma is the deadliest form of skin cancer. Although targeted therapies and immunotherapies have revolutionized the treatment of metastatic melanoma, most patients are not cured. Therapy resistance remains a significant clinical challenge. Melanoma comprises phenotypically distinct subpopulations of cells, exhibiting distinct gene signatures leading to tumor heterogeneity and favoring therapeutic resistance. Cellular plasticity in melanoma is referred to as phenotype switching. Regardless of their genomic classification, melanomas switch from a proliferative and differentiated phenotype to an invasive, dedifferentiated and often therapy-resistant state. In this review we discuss potential mechanisms underpinning melanoma phenotype switching, how this cellular plasticity contributes to resistance to both targeted therapies and immunotherapies. Finally, we highlight novel strategies to target plasticity and their potential clinical impact in melanoma.
Highlights
Melanoma is the deadliest form of skin cancer due to its high metastatic potential
A new paradigm termed “phenotype switching” emerged to better describe the plasticity of melanoma cells and their stem-like behavior. This model predicts that melanoma metastasis and phenotypic heterogeneity is driven by specific gene expression programs rather than by the accumulation of irreversible genetic events
While there are a number of subtypes of melanoma, including acral and mucosal, in this review we focus on cutaneous melanoma, with a short discussion of recent reports of plasticity in uveal melanoma
Summary
Melanoma is the deadliest form of skin cancer due to its high metastatic potential. Metastasis and therapy resistance of numerous tumor types is associated with intratumoral heterogeneity and cancer cell plasticity [1,2,3,4,5]. Gene expression analyses of cultured melanoma cells identified two predominant cell populations, exhibiting either ‘proliferative’ or ‘invasive’ phenotypes [6,7,8,9], reminiscent of the intratumoral heterogeneity present in patient-derived melanomas [10, 11]. Additional cell states have been defined with unique gene expression signatures, and differential therapeutic sensitivity and metastatic potential associated with each of these phenotypes (Figure 1) [14,15,16]
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