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

Abstract

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 molecular profiles. Remarkably, primary melanomas in women showed higher levels of antigen processing and presentation, and activation of the immune system response. Our results provide novel insights, relevant for developing personalized precision treatments for melanoma patients.

Proteogenomic Characterization Reveals Therapeutic Opportunities Related to Mitochondrial Function in Melanoma

“…Mitoribosomes were earlier proposed and used as potential targets for anticancer therapies (Kim et al, 2017; Lamb et al, 2015; Škrtić et al, 2011). Recently, in an observational study on primary melanomas, mitochondrial translation upregulation was discovered in the disease recurrence group (Gil et al, 2021). In the present study, we observed positive correlations between the levels of mitoribosomes and the proliferation status of the tumors at both protein and transcript levels, as previously reported (Akbani et al, 2015).…”

“…Mitoribosomes were earlier proposed and used as potential targets for anticancer therapies (Kim et al, 2017;Lamb et al, 2015;Škrtić et al, 2011). Recently, in an observational study on primary melanomas, mitochondrial translation upregulation was discovered in the disease recurrence group (Gil et al, 2021).…”

“…Interestingly, a large proteomic study revealed that tumors from patients responders to immunotherapy upregulated the OXPHOS and lipid metabolism (Harel et al, 2019). More recently, a small study on primary tumors revealed a progression dependence on the upregulation of mitochondrial ribosomes and oxidative phosphorylation (Gil et al, 2021). Thus, targeting mitochondrial functions is gaining attention in cancer treatment.…”

Mitochondrial and immune response dysregulation in melanoma recurrence

“…While our study cohort for nonrecurrent melanoma consisted exclusively of male, it is important to note that the identified risk factors for recurrence, characterized by downregulated immune response pathways, are considered gender-independent markers of recurrence risk. 4 Among the 166 significantly dysregulated proteins between tumour cell groups, a cluster of proteins involved in collagen formation, complement and coagulation cascades and immune response activities stood out with the highest score (Figure 4B). Additional immune response markers like CD1A were downregulated in recurrent cases.…”

“…Building upon our foundational work in the Human Melanoma Proteome Atlas, which extensively characterized melanoma presentations and molecular pathology, this study represents a significant advancement. [2][3][4] We now focus on a more targeted approach, isolating specific tumour regions to intricately investigate the interplay between tumour cells and the stromal component. This progression in our research strategy deepens our molecular understanding of the tumour microenvironment's significance in melanoma recurrence.…”