Arozarena and Wellbrock discuss phenotypic plasticity as a key process in melanoma progression and resistance to treatments, including immunotherapy. The two predominant transcriptional programs identified in cells and tumors are proliferative or invasive, characterized by MITFhigh or AXLhigh, respectively, and newer genomic technologies have revealed significant inter- and intra-tumor heterogeneity. Additional variables such as presence of CAF, TIL, mutational burden, ECM stiffness, and age influence plasticity, affecting treatment response and outcomes. Understanding these dynamic processes may offer additional treatment options.
Contributed by Katherine Turner
Malignant melanoma is notorious for its inter- and intratumour heterogeneity, based on transcriptionally distinct melanoma cell phenotypes. It is thought that these distinct phenotypes are plastic in nature and that their transcriptional reprogramming enables heterogeneous tumours both to undergo different stages of melanoma progression and to adjust to drug exposure during treatment. Recent advances in genomic technologies and the rapidly expanding availability of large gene expression datasets have allowed for a refined definition of the gene signatures that characterize these phenotypes and have revealed that phenotype plasticity plays a major role in the resistance to both targeted therapy and immunotherapy. In this Review we discuss the definition of melanoma phenotypes through particular transcriptional states and reveal the prognostic relevance of the related gene expression signatures. We review how the establishment of phenotypes is controlled and which roles phenotype plasticity plays in melanoma development and therapy. Because phenotype plasticity in melanoma bears a great resemblance to epithelial-mesenchymal transition, the lessons learned from melanoma will also benefit our understanding of other cancer types.