Focus on cutaneous and uveal melanoma specificities

Abstract

Cutaneous melanoma (CM) and uveal melanoma (UM) derive from cutaneous and uveal melanocytes that share the same embryonic origin and display the same cellular function. However, the etiopathogenesis and biological behaviors of these melanomas are very different. CM and UM display distinct landscapes of genetic alterations and show different metastatic routes and tropisms. Hence, therapeutic improvements achieved in the last few years for the treatment of CM have failed to ameliorate the clinical outcomes of patients with UM. The scope of this review is to discuss the differences in tumorigenic processes (etiologic factors and genetic alterations) and tumor biology (gene expression and signaling pathways) between CM and UM. We develop hypotheses to explain these differences, which might provide important clues for research avenues and the identification of actionable vulnerabilities suitable for the development of new therapeutic strategies for metastatic UM.

Keywords: cancer; melanoma; skin.

Figure 1.

Main genetic and signaling pathway alterations in UMs and CMs. Signaling modules implicated in CMs (blue box), UMs (orange boxes), and both lesions (gray box). Gain-of-function (red) and loss-of-function (green) mutations are indicated as well as genes mutated in both UM and CM (yellow star). In CM, growth factor binding to receptor tyrosine kinase or mutations trigger the activation of the RAS (Rous sarcoma)–BRAF–MEK–ERK (extracellular regulated kinase) and/or PI3K–AKT (protein kinase B)–mTOR signaling cascades. In UM, ligand binding to G-protein-coupled receptors (GPCRs), among which is CYSLTR2 (cysteinyl leukotriene receptor 2), enables GNAQ/11 [guanine nucleotide-binding protein G(q) subunit α/guanine nucleotide-binding protein subunit α-11] to signal to downstream effectors such as ARF6 (ADP-ribosylation factor 6), TRIO, and PLCβ (phospholipase C β) and triggers activation of multiple signaling pathways. These pathways include the TRIO–RHO–RAC (Ras-related C3 botulinum toxin)–YAP (yes-associated protein) cascade, which is involved in actin cytoskeleton reorganization and PKC (protein kinase C)–ERK, which controls cell proliferation. Moreover, BAP1, which is lost in a large proportion of UM, controls DNA integrity, proliferation, and survival of melanoma cells, the dysregulation of which is involved in transformation. Note that GNAQ/11 and BAP1 are also affected to a lesser extent in CMs.