Improved survival prognostication of node-positive malignant melanoma patients utilizing shotgun proteomics guided by histopathological characterization and genomic data

Betancourt, Lázaro; Pawłowski, Krzysztof; Eriksson, Jonatan; Szász, Attila Marcell; Mitra, Shamik; Pla, Indira; Welinder, Charlotte; Ekedahl, Henrik; Broberg, Per; Appelqvist, Roger; Yakovleva, Maria; Sugita, Y.; Miharada, Kenichi; Ingvar, Christian; Lundgren, Lotta; Baldetorp, Bo; Olsson, Håkan; Rezeli, Melinda; Wieslander, Elisabet; Horvatovich, Péter; Malm, Johan; Jönsson, Göran; Markó-Varga, György

doi:10.1038/s41598-019-41625-z

Cited by 14 publications

(17 citation statements)

References 106 publications

(103 reference statements)

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“…Moreover, inflammatory process and cancer development are inter-connected, positioning acutephase proteins as potential biomarkers in several types of cancer 36. Some members of these plasma proteins are prognostic serum/plasma biomarkers (LDH 37 , e.g., Serum amyloid A 36,38,39 ), with increased expression in patients with short survival (CRP 36,40 , as well as ORM1 41 ). Notably, all these proteins were identified as upregulated in the medium-high/high proliferative groups, which indicates a correlation to tumor cell proliferation.…”

Section: Melanoma Proliferation Relies On Repressing the Immune System Response-related Pathwaysmentioning

confidence: 99%

Proteogenomics Reveals how Metastatic Melanoma Modulates the Immune System to Allow Immune Evasion

Kim

Szeitz

et al. 2021

Preprint

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Malignant melanoma (MM) develops from the melanocytes and in its advanced stage is the most aggressive type of skin cancer. Here we report a comprehensive analysis on a prospective cohort study, including non-tumor, primary and metastasis tissues (n=77) with the corresponding plasma samples (n=56) from patients with malignant melanoma. The tumors and surrounding tissues were characterized with a combination of high-throughput analyses including quantitative proteomics, phosphoproteomics, acetylomics, and whole exome sequencing (WES) combined with in-depth histopathology analysis. Melanoma cell proliferation highly correlates with dysregulation at the proteome, at the posttranslational- and at the transcriptome level. Some of the changes were also verified in the plasma proteome. The metabolic reprogramming in melanoma includes upregulation of the glycolysis and the oxidative phosphorylation, and an increase in glutamine consumption, while downregulated proteins involved in the degradation of amino acids, fatty acids, and the extracellular matrix (ECM) receptor interaction. The pathways most dysregulated in MM including the MAP kinases-, the PI3K-AKT signaling, and the calcium homeostasis, are among the most affected by mutations, thus, dysregulation in these pathways can be manifested as drivers in melanoma development and progression. The phosphoproteome analysis combined with target-based prediction mapped 75% of the human kinome. Melanoma cell proliferation was driven by two key factors: i) metabolic reprogramming leading to upregulation of the glycolysis and oxidative phosphorylation, supported by HIF-1 signaling pathway and mitochondrial translation; and ii) a dysregulation of the immune system response, which was mirrored by immune system processes in the plasma proteome. Regulation of the melanoma acetylome and expression of deacetylase enzymes discriminated between groups based on tissue origin and proliferation, indicating a way to guide the successful use of HDAC inhibitors in melanoma. The disease progression toward metastasis is driven by the downregulation of the immune system response, including MHC class I and II, which allows tumors to evade immune surveillance. Altogether, new evidence is provided at different molecular levels to allow improved understanding of the melanoma progression, ultimately contributing to better treatment strategies.

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Section: Melanoma Proliferation Relies On Repressing the Immune System Response-related Pathwaysmentioning

confidence: 99%

Proteogenomics Reveals how Metastatic Melanoma Modulates the Immune System to Allow Immune Evasion

Kim

Szeitz

et al. 2021

Preprint

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“…Direct sequencing cDNA (ds-cDNA) was performed as previously described [14]. Briefly, mRNA was extracted from frozen melanoma tissue specimens and cDNA was synthesized.…”

Section: Braf V600e Mutation Testingmentioning

confidence: 99%

“…Proteomics is a highly-promising field of research that can assist in identifying therapeutic targets and cancer biomarkers [11][12][13][14][15]. At the core of proteomics is the technique of mass spectrometry (MS) that provides a sensitive analysis of complex mixtures of proteins and peptides.…”

Section: Introductionmentioning

confidence: 99%

The Hidden Story of Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma—Association with Clinical Outcome and Tumor Phenotypes

Betancourt

Szász

Kuras

et al. 2019

Cancers

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In comparison to other human cancer types, malignant melanoma exhibits the greatest amount of heterogeneity. After DNA-based detection of the BRAF V600E mutation in melanoma patients, targeted inhibitor treatment is the current recommendation. This approach, however, does not take the abundance of the therapeutic target, i.e., the B-raf V600E protein, into consideration. As shown by immunohistochemistry, the protein expression profiles of metastatic melanomas clearly reveal the existence of inter- and intra-tumor variability. Nevertheless, the technique is only semi-quantitative. To quantitate the mutant protein there is a fundamental need for more precise techniques that are aimed at defining the currently non-existent link between the levels of the target protein and subsequent drug efficacy. Using cutting-edge mass spectrometry combined with DNA and mRNA sequencing, the mutated B-raf protein within metastatic tumors was quantitated for the first time. B-raf V600E protein analysis revealed a subjacent layer of heterogeneity for mutation-positive metastatic melanomas. These were characterized into two distinct groups with different tumor morphologies, protein profiles and patient clinical outcomes. This study provides evidence that a higher level of expression in the mutated protein is associated with a more aggressive tumor progression. Our study design, comprised of surgical isolation of tumors, histopathological characterization, tissue biobanking, and protein analysis, may enable the eventual delineation of patient responders/non-responders and subsequent therapy for malignant melanoma.

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“…Our biobank coupled high-end proteomic platform was used to study the melanoma tumour tissues (Welinder et al 2015(Welinder et al , 2017Welinder et al, 2014a, b;Gil et al 2019;Kuras et al 2018;Murillo et al 2018). We used histopathological characterisation and a genomic data-directed proteomic strategy to successfully identify a protein expression pattern that was associated with improved survival prognostics in lymph node samples from stage 3 malignant melanoma patients (Betancourt et al 2019). A progression from locoregional to distantly spread disease was witnessed throughout the years (Fig.…”

Section: Introductionmentioning

confidence: 99%

Novel functional proteins coded by the human genome discovered in metastases of melanoma patients

et al. 2019

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In the advanced stages, malignant melanoma (MM) has a very poor prognosis. Due to tremendous efforts in cancer research over the last 10 years, and the introduction of novel therapies such as targeted therapies and immunomodulators, the rather dark horizon of the median survival has dramatically changed from under 1 year to several years. With the advent of proteomics, deep-mining studies can reach low-abundant expression levels. The complexity of the proteome, however, still surpasses the dynamic range capabilities of current analytical techniques. Consequently, many predicted protein products with potential biological Cell Biol Toxicol

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Improved survival prognostication of node-positive malignant melanoma patients utilizing shotgun proteomics guided by histopathological characterization and genomic data

Cited by 14 publications

References 106 publications

Proteogenomics Reveals how Metastatic Melanoma Modulates the Immune System to Allow Immune Evasion

Proteogenomics Reveals how Metastatic Melanoma Modulates the Immune System to Allow Immune Evasion

The Hidden Story of Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma—Association with Clinical Outcome and Tumor Phenotypes

Novel functional proteins coded by the human genome discovered in metastases of melanoma patients

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