Targeting GPCRs and Their Signaling as a Therapeutic Option in Melanoma

Abstract

G-protein-coupled receptors (GPCRs) serve prominent roles in melanocyte lineage physiology, with an impact at all stages of development, as well as on mature melanocyte functions. GPCR ligands are present in the skin and regulate melanocyte homeostasis, including pigmentation. The role of GPCRs in the regulation of pigmentation and, consequently, protection against external aggression, such as ultraviolet radiation, has long been established. However, evidence of new functions of GPCRs directly in melanomagenesis has been highlighted in recent years. GPCRs are coupled, through their intracellular domains, to heterotrimeric G-proteins, which induce cellular signaling through various pathways. Such signaling modulates numerous essential cellular processes that occur during melanomagenesis, including proliferation and migration. GPCR-associated signaling in melanoma can be activated by the binding of paracrine factors to their receptors or directly by activating mutations. In this review, we present melanoma-associated alterations of GPCRs and their downstream signaling and discuss the various preclinical models used to evaluate new therapeutic approaches against GPCR activity in melanoma. Recent striking advances in our understanding of the structure, function, and regulation of GPCRs will undoubtedly broaden melanoma treatment options in the future.

DNA Methylation Signatures Correlate with Response to Immune Checkpoint Inhibitors in Metastatic Melanoma

“…The most enriched pathways were related to olfactory pathways such as “detection of chemical stimulus involved in sensory perception of smell” with an enrichment false discovery rate of 6.13E−45, followed by “sensory perception of smell” and “detection of chemical stimulus involved in sensory perception” detected by GO:BP and “olfactory receptor activity” by GO:MF, which were recently demonstrated to be involved in the cell proliferation and migration processes of primary melanoma and melanoma metastasis [ 14 ]. Additionally, GO:BP and GO:MF revealed enrichments in “G protein-coupled receptor signaling pathways,” which were demonstrated to be involved in skin cancer development [ 32 ] and were shown to be engaged in melanogenesis including proliferation and migration [ 34 ]. Furthermore, GO:BP, GO:MF, and GO:CC displayed enrichments related to epidermal keratinocytes such as “keratinocyte differentiation,” “epidermis development,” “keratin filament,” and “intermediate filament cytoskeleton” (Table 2 ), indicative of an crosstalk between melanoma cells and the surrounding tumor microenvironment [ 21 ].…”

“…In addition, our pathway analysis provides further insights into the potentially differentially regulated pathways between responders and non-responders. Enrichments were detected in olfactory and G-protein coupled receptor signaling pathways, which were recently associated with migration and proliferation processes in melanoma [ 14 , 34 ], as well as enrichments in the humoral response, which were shown to be supportive for ICI responses in metastatic melanoma [ 17 ].…”

Low Expression of CLEC2B Indicates Poor Prognosis in Melanoma

“…In melanoma, GPCR-mediated signal transduction is activated by combining paracrine factors and their receptors or by activating mutations to promote proliferation, invasion, and migration. 13 , 14 In addition, the interleukin signaling pathway is also implicated in the treatment of melanoma. Various interleukins inhibit melanoma development by regulating the tumor microenvironment’s immunity and inflammation, 15–17 suggesting a possible role of CLEC2B in the immune response of melanoma.…”

The E-cadherin-ESR1-GRPR axis defines a sex-specific metastatic pathway in melanoma

“…This strategy could thus be applied to other cancers, notably to hinder the formation of lung melanoma metastases in women. GPCRs are widely targeted, but their targeting is still underutilized in cancer 51, 52 . Here, we identified GRPR as a major player in cancer progression.…”