Understanding Molecular Mechanisms of Phenotype Switching and Crosstalk with TME to Reveal New Vulnerabilities of Melanoma

Abstract

Melanoma cells are notorious for their high plasticity and ability to switch back and forth between various melanoma cell states, enabling the adaptation to sub-optimal conditions and therapeutics. This phenotypic plasticity, which has gained more attention in cancer research, is proposed as a new paradigm for melanoma progression. In this review, we provide a detailed and deep comprehensive recapitulation of the complex spectrum of phenotype switching in melanoma, the key regulator factors, the various and new melanoma states, and corresponding signatures. We also present an extensive description of the role of epigenetic modifications (chromatin remodeling, methylation, and activities of long non-coding RNAs/miRNAs) and metabolic rewiring in the dynamic switch. Furthermore, we elucidate the main role of the crosstalk between the tumor microenvironment (TME) and oxidative stress in the regulation of the phenotype switching. Finally, we discuss in detail several rational therapeutic approaches, such as exploiting phenotype-specific and metabolic vulnerabilities and targeting components and signals of the TME, to improve the response of melanoma patients to treatments.

ATP1A1 is a promising new target for melanoma treatment and can be inhibited by its physiological ligand bufalin to restore targeted therapy efficacy

“…To further characterize the role of ATP1A1 in melanoma, we conducted an analysis using the cBioPortal for Cancer Genomics (http://www.cbioportal.org/) based on data from The Cancer Genome Atlas (TCGA) of 448 cutaneous melanoma samples from the PanCancer Atlas. Our analysis revealed a positive correlation between high ATP1A1 mRNA expression and a panel of markers associated with differentiation and pigmentation, including MITF, TYR, TYRP1, TYRP2/DCT, RAB27A, SOX10, PAX3, and MLANA (Figure 1D) [29]. On the contrary, we observed a negative correlation between ATP1A1 expression and markers associated with a mesenchymal/invasive phenotype, such as AXL, EGFR, ZEB1, WNT5A, TGFβ1, SNAI1, MMP9, and TWIST2.…”

ATP1A1 is a promising new target for melanoma treatment and can be inhibited by its physiological ligand bufalin to restore targeted therapy efficacy

“…Our analysis revealed a positive correlation between high ATP1A1 mRNA expression and a panel of markers associated with differentiation and pigmentation, including MITF, TYR, TYRP1, TYRP2/DCT, RAB27A, SOX10, PAX3, and MLANA (Fig. 1 D) [ 29 ]. On the contrary, we observed a negative correlation between ATP1A1 expression and markers associated with a mesenchymal/invasive phenotype, such as AXL, EGFR, ZEB1, WNT5A, TGFβ1, SNAI1, MMP9, and TWIST2.…”

ROR2, a driver of “phenotype switching” in melanoma?

“…In contrast, the biochemical function of ROR2, a tyrosine kinase receptor (TKR), is completely different, a fact that can be viewed as an impediment to regulating "phenotype switching". However, similar to other TKR important in melanoma such as AXL and EGFR [13], ROR2 does alter the expression of numerous proteins in melanoma [3][4][5] and other cancers [14]. Although the precise mechanism has not been completely elucidated, the signal triggered by aberrant ROR2 expression can be transduced by different signaling pathways and modulate transcription factor activity (i.e.…”