An Observational Study on the Molecular Profiling of Primary Melanomas Reveals a Progression Dependence on Mitochondrial Activation

Simple Summary Malignant melanoma is the deadliest among the skin cancers. In the advanced stage, it shows extremely poor prognosis. The incidence and mortality of melanoma has been continuously increasing worldwide, primarily among the fair-skinned populations. To date, the best indicator for progression is the tumor thickness (Breslow). In this sense, there is a fundamental need to discover early indicators of disease progression. We believe that in-depth molecular profiling at the multiomic level of primary melanomas may find a signature that predicts disease progression toward metastasis. Here we report an observational study of a small primary melanoma cohort, in which in-depth molecular profiling was performed at the levels of protein expression, phosphorylation, and lysine acetylation. Our results provided evidence for dysregulation of pathways and biological processes at all molecular levels evaluated, in primary tumors from patients that ultimately developed a metastatic disease. Moreover, we provided evidence at the molecular level of the sex-related differences in the melanoma disease presentation. Melanoma in advanced stages is one of the most aggressive tumors and the deadliest of skin cancers. To date, the histopathological staging focuses on tumor thickness, and clinical staging is a major estimate of the clinical behavior of primary melanoma. Here we report on an observational study with in-depth molecular profiling at the protein level including post-translational modifications (PTMs) on eleven primary tumors from melanoma patients. Global proteomics, phosphoproteomics, and acetylomics were performed on each sample. We observed an up-regulation of key mitochondrial functions, including the mitochondrial translation machinery and the down-regulation of structural proteins involved in cell adhesion, the cytoskeleton organization, and epidermis development, which dictates the progression of the disease. Additionally, the PTM level pathways related to RNA processing and transport, as well as chromatin organization, were dysregulated in relation to the progression of melanoma. Most of the pathways dysregulated in this cohort were enriched in genes differentially expressed at the transcript level when similar groups are compared or metastasis to primary melanomas. At the genome level, we found significant differences in the mutation profiles between metastatic and primary melanomas. Our findings also highlighted sex-related differences in the mo