Abstract
Cutaneous melanoma represents one of the deadliest types of skin cancer. The prognosis strongly depends on the disease stage, thus early detection is crucial. New therapies, including BRAF and MEK inhibitors and immunotherapies, have significantly improved the survival of patients in the last decade. However, intrinsic and acquired resistance is still a challenge. In this review, we discuss two major aspects that contribute to the aggressiveness of melanoma, namely, the embryonic origin of melanocytes and melanoma cells and cellular plasticity. First, we summarize the physiological function of epidermal melanocytes and their development from precursor cells that originate from the neural crest (NC). Next, we discuss the concepts of intratumoral heterogeneity, cellular plasticity, and phenotype switching that enable melanoma to adapt to changes in the tumor microenvironment and promote disease progression and drug resistance. Finally, we further dissect the connection of these two aspects by focusing on the transcriptional regulators MSX1, MITF, SOX10, PAX3, and FOXD3. These factors play a key role in NC initiation, NC cell migration, and melanocyte formation, and we discuss how they contribute to cellular plasticity and drug resistance in melanoma.
Highlights
Cutaneous melanoma represents one of the deadliest types of skin cancer globally with 55,500 deaths annually [1]
The prognosis strongly depends on the stage of the disease, underlining that early detection of melanoma is of paramount importance for a good prognosis
These results indicate that transforming growth factor- β (TGF-β) may be one of the factors mediating phenotype switching from a proliferative to a more invasive phenotype
Summary
Cutaneous melanoma represents one of the deadliest types of skin cancer globally with 55,500 deaths annually [1]. Five-year overall survival (OS) rates of stage I melanoma patients are almost 100% [7]. Five-year OS rates are only around 20% for patients with stage IV melanoma [8]. New systemic therapy approaches targeting immune checkpoint blocking antibodies and small moleculeinhibitors targeting mutant BRAF kinase and its downstream target MEK have drastically changed the landscape of melanoma therapy in the last decade. These treatment options seem to significantly improve the survival of patients with advanced melanoma as recently shown [9,10,11]. Drug resistance is not uncommon and poses a major challenge for long-term survival [1]
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