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Functional and clinical impact of ARL15 in cutaneous melanoma aggressiveness
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Resumo(s)
Cutaneous melanoma (CM) is the deadliest form of skin cancer despite accounting for less than
1% of cases. Although very treatable in early stages, advanced-stage CM has an abysmal survival rate
mostly attributed to its high propensity for metastasis, making timely detection and adequate disease
management critical.
CM often presents with alterations in key cell signalling pathways such as in
Ras/Raf/MEK/ERK (MAPK) and PI3K/Akt/mTOR (PI3K). In fact, more than 60% of CMs show
aberrant activation of the MAPK pathway, frequently due to BRAF gene mutations. The downstream
activation of these pathways is mainly facilitated by members of the molecular switch Ras superfamily
of small GTPases, including ARL proteins, whose role in CM remains relatively unexplored. These
pathways are essential for tumour progression as they are involved in membrane trafficking and
cytoskeleton organization, critical mechanisms of cancer migration and invasion.
Our research group found ARL GTPases to be aberrantly expressed in a previous in-silico
analysis of CM data of The Cancer Genome Atlas network, with ARL15 being significantly
downregulated compared to normal skin samples. ARL15 expression was also found to be correlated
with a specific immune profile of CM patients and presented as an independent predictor of patient
survival in the same study. We therefore sought to validate these findings in a cohort of IPOLFG patients,
as well as investigate the role of ARL15 on the mechanisms behind CM aggressiveness using in vitro
assays.
Our results confirm that ARL15 is downregulated in CM and even more so in late-stage disease.
However, we were unable to establish a correlation between ARL15 expression and patient prognosis in
our samples thus far. Furthermore, we noted a statistically significant correlation between ARL15
expression and tumour-infiltrating Treg-like cells,suggesting a potential role for ARL15 in the modulation
of the immune response in CM. However, a precise molecular characterisation of these cells must be
performed in order to understand the mechanisms underlying this correlation. Notably, lentiviral
knockdown of ARL15 in two distinct BRAF-mutant CM cell lines resulted in increased migratory and
invasive capacities of cells, with no noticeable changes in cell viability.
Taken together, these findings seem to suggest that ARL15 could be an important factor in the
aggressiveness of CM, having a putative role as a tumour suppressor. While our study provides important
insights into the potential role of ARL15 in CM, further research is needed to fully understand its
mechanisms and effects on clinical outcomes. Nonetheless, the significance of this study could have
broader implications for cancer research, as ARL proteins are dysregulated in many types of cancer and
can therefore serve as potential biomarkers and therapeutic targets.
Descrição
Tese de mestrado, Biologia Molecular e Genética, 2023, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
pequenas GTPases ADP ribosylation factor-like via de sinalização MAPK via de sinalização PI3K supressor de tumores biomarcadores invasão Teses de mestrado - 2023