Subversion of Ras Small GTPases in Cutaneous Melanoma Aggressiveness

Abstract

The rising incidence and mortality rate associated with the metastatic ability of cutaneous melanoma represent a major public health concern. Cutaneous melanoma is one of the most invasive human cancers, but the molecular mechanisms are poorly understood. Moreover, currently available therapies are not efficient in avoiding melanoma lethality. In this context, new biomarkers of prognosis, metastasis, and response to therapy are necessary to better predict the disease outcome. Additionally, the knowledge about the molecular alterations and dysregulated pathways involved in melanoma metastasis may provide new therapeutic targets. Members of the Ras superfamily of small GTPases regulate various essential cellular activities, from signaling to membrane traffic and cytoskeleton dynamics. Therefore, it is not surprising that they are differentially expressed, and their functions subverted in several types of cancer, including melanoma. Indeed, Ras small GTPases were found to regulate melanoma progression and invasion. Hence, a better understanding of the mechanisms regulated by Ras small GTPases that are involved in melanoma tumorigenesis and progression may provide new therapeutic strategies to block these processes. Here, we review the current knowledge on the role of Ras small GTPases in melanoma aggressiveness and the molecular mechanisms involved. Furthermore, we summarize the known involvement of these proteins in melanoma metastasis and how these players influence the response to therapy.

Unraveling the Relevance of ARL GTPases in Cutaneous Melanoma Prognosis through Integrated Bioinformatics Analysis

“…Despite the remarkable efforts to improve our understanding of CM biology, there is still a need to identify new biomarkers to further stratify patients based on prognosis, metastatic propensity, and response to therapy [15]. Unfortunately, current knowledge about ARF family members in CM is limited, and in particular, ARL proteins' involvement in CM etiology and progression remains unknown [26]. Hence, we evaluated the effect of ARL expression in prognosis, immune microenvironment modification, and their functional interactions with well-established signaling pathways in CM by performing an integrative analysis of open access databases.…”

“…In contrast to Arf proteins, the biochemical and functional characterization of Arls under physiological and pathological conditions is poorly explored [26]. The physiological functions of most Arls are still unclear.…”

“…To the best our knowledge, this is the only study exploring the role of an ARL gene in CM. Considering the multiplicity of physiological processes in which ARL proteins are involved, and their impact on the growth and metastatic ability of several types of cancer, it is likely that they play important roles in CM tumorigenesis and progression [26]. However, the role of these proteins in cancer remains poorly explored, and specifically in CM, there are almost no data about the relevance of ARL GTPases.…”

Immune escape and metastasis mechanisms in melanoma: breaking down the dichotomy

“…Current immunotherapies for advanced stage melanomas involve antagonization of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4, ipilimumab) and programmed cell death protein-1 (PD-1, nivolumab and pembrolizumab), but in 45-70% of cases these therapies encounter primary resistance ( Table 1 ) ( 5 , 11 ). Further, immunotherapies with initially promising responses eventually yield to cancer progression in ~20-30% of respondents as secondary resistance occurs ( 5 , 13 , 14 ). Moreover, relatively high recurrence rates persist among patients treated with immunotherapies and the 5-year survival rate for advanced melanoma rests around 40% ( 1 , 9 , 10 ).…”

Targeted Quantitative Profiling of GTP-Binding Proteins Associated with Metastasis of Melanoma Cells

“…GTP-binding proteins serve as molecular switches in cell signaling pathways . Aberrant expression and/or activities of GTP-binding proteins, including small GTPases, are known to be associated with melanoma metastasis. , Huang et al reported a targeted proteomic method combining stable isotope labeling by amino acids in cell culture (SILAC), sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (PAGE) fractionation, and multiple-reaction monitoring (MRM) analysis, to quantify small GTPases in matched pairs of primary/metastatic melanoma cells. Based on liquid chromatography (LC)–mass spectrometry (MS)/MS and bioinformatic analysis, they revealed a potential role of RAB38 in enhancing melanoma metastasis through the upregulation of matrix metalloproteinase 2 (MMP2) and MMP9.…”