Melanoma proteomics suggests functional differences related to mutational status

Abstract

Melanoma is the most lethal cutaneous cancer. New drugs have recently appeared; however, not all patients obtain a benefit of these new drugs. For this reason, it is still necessary to characterize melanoma at molecular level. The aim of this study was to explore the molecular differences between melanoma tumor subtypes, based on BRAF and NRAS mutational status. Fourteen formalin-fixed, paraffin-embedded melanoma samples were analyzed using a high-throughput proteomics approach, combined with probabilistic graphical models and Flux Balance Analysis, to characterize these differences. Proteomics analyses showed differences in expression of proteins related with fatty acid metabolism, melanogenesis and extracellular space between BRAF mutated and BRAF non-mutated melanoma tumors. Additionally, probabilistic graphical models showed differences between melanoma subgroups at biological processes such as melanogenesis or metabolism. On the other hand, Flux Balance Analysis predicts a higher tumor growth rate in BRAF mutated melanoma samples. In conclusion, differential biological processes between melanomas showing a specific mutational status can be detected using combined proteomics and computational approaches.

The human melanoma proteome atlas—Defining the molecular pathology

“…A statistically significant difference ( t ‐test, FDR 0.05) between the two groups was seen for only two proteins. A recent study, although with fewer samples, only found 17 differentially expressed proteins when compared the protein expression between BRAF mutated and WT tumors 51 . The results suggest that tumors with the BRAF V600E mutation does not display a specific proteomic profile when compared to WT BRAF tumor.…”

“…A recent study, although with fewer samples, only found 17 differentially expressed proteins when compared the protein expression between BRAF mutated and WT tumors. 51 The results suggest that tumors with the BRAF V600E mutation does not display a specific proteomic profile when compared to WT BRAF tumor. Nevertheless, we recently reported that the level of expression of the mutation does cause a different proteome profile within BRAF V600E positive tumors, which also correlates with differences in tissue morphology and patient outcome.…”

Towards Precision Dermatology: Emerging Role of Proteomic Analysis of the Skin

“…Genetic and molecular characterization of melanoma has recently led to the development of targeted treatments, such as immunotherapy and treatments targeting the BRAF/MEK pathway. For patients with metastatic melanoma, these treatments have fundamentally changed the prognosis of disease [32,38,41]. MS-based proteomic analyses have enabled further characterization of melanoma tumor biology, including the molecular alterations associated with different stages of disease and mutational status.…”

BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy

“…These alterations are essential to support uncontrolled growth, evasion of inhibitory signals for tumor growth, cell migration and metastasis to distant tissues. Regarding RAS pathway activation, it has been demonstrated that BRAF V600E contributes to melanoma cell survival under oxidative metabolic stress conditions through PCG1α and MITF 12 – 15 and to metabolic rewiring 16 , in which the BRAF V600E mutant melanomas seemed to downregulate the expression of proteins related to fatty acid metabolism 17 . In addition, upon BRAF V600E activation, RSK1 promotes glycolytic metabolism through the phosphorylation of PFKFB2, probably in a cell type-dependent manner 18 .…”