Exploring the Complex and Multifaceted Interplay between Melanoma Cells and the Tumor Microenvironment

Abstract

Malignant melanoma is a very aggressive skin cancer, characterized by a heterogeneous nature and high metastatic potential. The incidence of melanoma is continuously increasing worldwide, and it is one of the most common cancers in young adults. In the past twenty years, our understanding of melanoma biology has increased profoundly, and disease management for patients with disseminated disease has improved due to the emergence of immunotherapy and targeted therapy. However, a significant fraction of patients relapse or do not respond adequately to treatment. This can partly be explained by the complex signaling between the tumor and its microenvironment, giving rise to melanoma phenotypes with different patterns of disease progression. This review focuses on the key aspects and complex relationship between pathogenesis, genetic abnormalities, tumor microenvironment, cellular plasticity, and metabolic reprogramming in melanoma. By acquiring a deeper understanding of the multifaceted features of melanomagenesis, we can reach a point of more individualized and patient-centered disease management and reduced costs of ineffective treatments.

Malignant Melanoma: An Overview, New Perspectives, and Vitamin D Signaling

“…Malignant transformation of melanocytes with further progression to advanced stages, collectively called melanomagenesis, is initiated and driven by environmental, genetic (inheritable), constitutional, and epigenetic factors, as well as by acquired mutations with the accumulation of genomic changes further amplified by local and systemic neuroimmunoendocrine factors affecting progression of the disease [ 1 , 2 , 4 , 6 , 9 , 11 , 12 , 13 , 14 , 30 , 32 , 50 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. Since these factors have been discussed in many review articles, we will only provide a brief overview of them.…”

“…The pathological and clinical staging allows precise prediction of the natural history of the disease, including overall survival (OS) and disease-free survival (DF) times, and when supplemented by ancillary studies (IHC) or molecular testing (GP, GEP, NEGS) form a basis for an educated selection of appropriate therapeutic approaches. It must be noted that the staging of melanoma would likely be modified and/or supplemented by deposited RNA sequencing data, proteomic data, or metabolomic data at publicly available databases with implications for future therapy [ 1 , 11 , 18 , 30 , 48 , 74 , 75 , 76 , 77 , 79 , 127 , 130 , 134 , 159 , 165 , 169 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 ]. This will be further discussed in Section 5.5 : Bioinformatics Considerations of Melanoma Diagnosis and Treatment.…”

“…The developing resistance to targeted- or immuno-therapy leading to recurrent disease and death of the patient represents a significant challenge. There are different mechanisms underlying this negative phenomenon, including tumor heterogeneity with pre-existing mutations allowing clonal expansion of resistant cells, mutations during therapy and progression of the disease, mutator phenotype, metabolic heterogeneity, and dynamic changes in the tumor microenvironment, to name a few [ 4 , 6 , 25 , 30 , 37 , 74 , 75 , 87 , 130 , 165 , 178 , 179 , 182 , 211 , 218 , 229 , 230 , 231 , 232 , 233 ]. It must be noted that melanoma itself can affect the host response at local and systemic levels through production of neurohormonal regulators (as expected because of the neural crest origin of melanocytes) with immunosuppressive properties [ 3 , 50 , 82 , 234 ], including intermediates of melanogenesis and melanin that would increase resistance to any type of therapy [ 4 , 235 , 236 ].…”

Regression of metastatic malignant melanoma with dupilumab: A case report

“…For patients with disseminated disease however, the outcomes are still poor despite the recent emergence of immune checkpoint inhibitors and targeted treatments. 7 We present the case of a 75-year-old male diagnosed with BRAF negative stage IV malignant melanoma who developed flare-up of AD responsive to dupilumab. Radiologically confirmed metastases to the lung, liver and pleura had cleared 1 year after commencement of dupilumab.…”

“…For patients with disseminated disease however, the outcomes are still poor despite the recent emergence of immune checkpoint inhibitors and targeted treatments. 7 …”