Challenging the heterogeneity of disease presentation in malignant melanoma—impact on patient treatment

Szász, Attila Marcell; Malm, Johan; Rezeli, Melinda; Sugita, Y.; Betancourt, Lázaro; Rivas, Daniel; Győrffy, Balázs; Markó-Varga, György

doi:10.1007/s10565-018-9446-9

Cited by 17 publications

(8 citation statements)

References 52 publications

(55 reference statements)

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“…The results acquired from cell line-based studies do not necessarily reflect the complexity of the disease. Exploring MM in patient tumors is crucial because the heterogeneity of the tissue and the microenvironment of the surrounding cells is taken into consideration [5–7]. In addition, the analysis of individual patients could be integrated with clinical data to acquire more reliable information on biomarker candidates [4].…”

Section: Introductionmentioning

confidence: 99%

Automated phosphopeptide enrichment from minute quantities of frozen malignant melanoma tissue

et al. 2018

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To acquire a deeper understanding of malignant melanoma (MM), it is essential to study the proteome of patient tissues. In particular, phosphoproteomics of MM has become of significant importance because of the central role that phosphorylation plays in the development of MM. Investigating clinical samples, however, is an extremely challenging task as there is usually only very limited quantities of material available to perform targeted enrichment approaches. Here, an automated phosphopeptide enrichment protocol using the AssayMap Bravo platform was applied to MM tissues and assessed for performance. The strategy proved to be highly-sensitive, less prone to variability, less laborious than existing techniques and adequate for starting quantities at the microgram level. An Fe(III)-NTA-IMACbased enrichment workflow was applied to a dilution series of MM tissue lysates. The workflow was efficient in terms of sensitivity, reproducibility and phosphosite localization; and from only 12.5 μg of sample, more than 1,000 phosphopeptides were identified. In addition, from 60 μg of protein material the number of identified phosphoproteins from individual MM samples was comparable to previous reports that used extensive fractionation methods. Our data set included key pathways that are involved in MM progression; such as MAPK, melanocyte development and integrin signaling. Moreover, tissue-specific immunological proteins were identified, that have not been previously observed in the proteome of MMderived cell lines. In conclusion, this workflow is suitable to study large cohorts of clinical samples that demand automatic and careful handling.

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Section: Introductionmentioning

confidence: 99%

Automated phosphopeptide enrichment from minute quantities of frozen malignant melanoma tissue

et al. 2018

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“…The tumorigenesis and progression of melanoma is a complex and multistep process that results from interactions between chromosomal abnormalities, translocations, gene mutations, epigenetic changes and environmental factors (6,27). Patients who acquire melanoma at an early stage could be treated with surgical management; however, patients at advanced stages respond poorly to current treatments (28,29). Although the understanding of the molecular mechanisms involved in the pathogenesis of melanoma and the myriad of treatment studies have rapidly advanced over the past two decades, effective early diagnostic technologies and systemic therapeutic strategies of this disease remain unsatisfactory, presenting a five-year survival rate <15% (30).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of microRNA‑21 inhibits the growth and metastasis of melanoma cells by targeting MKK3

Zhou

Yu²,

Jing³

et al. 2019

Mol Med Report

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Melanoma is an aggressive skin carcinoma with poor prognosis, and is prevalent worldwide. It was demonstrated that microRNA (miR)-21 and mitogen-activated protein kinase kinase 3 (MKK3) both participated in the occurrence and development of various tumors; however, their detailed roles in the progression of melanoma remain unclear. Reverse transcription-quantitative PCR (RT-qPCR) and western blot analyses were conducted to examine the expression levels of miR-21 and MKK3 in clinical specimens of patients with melanoma and melanoma cell lines. A dual-luciferase reporter assay was performed to verify the target interaction between miR-21 and MKK3. The mRNA and protein expressions of MKK3 were measured using RT-qPCR and western blot analysis, respectively, following transfection with miR-21 mimics and inhibitor. Subsequently, Cell Counting Kit-8 and colony formation assays, and flow cytometry were conducted to assess the effects of miR-21 and MKK3 on the cell growth of melanoma. Cell migration and invasion experiments were performed to evaluate the effects of miR-21 and MKK3 on the cell metastasis of melanoma. It was revealed that MKK3 was upregulated, and miR-21 was downregulated in patients with melanoma and melanoma cell lines. MKK3 was demonstrated to be a direct target of miR-21. Furthermore, it was demonstrated that upregulated miR-21 expression and downregulated MKK3 expression suppressed cell proliferation and colony formation, promoted apoptosis, delayed the cell cycle, and inhibited cell migration and invasion. The present findings suggested that miR-21 could inhibit the cell growth and metastasis of melanoma by negatively regulating MKK3.

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“…To characterise the MM phosphoproteome in detail, and to discover biomarkers of clinical significance, large MM patient tissue cohorts are required. Unlike cell lines, patient tissue takes into account the heterogeneity of the tumours and the microenvironment of the surrounding cells (Marcell Szasz et al 2018;Szász et al 2017). This, however, raises additional challenges such as reproducibility, low quantities of available starting material, material loss and lack of automation.…”

Section: Pathway Signalling and Protein Phosphorylationmentioning

confidence: 99%

Clinical protein science in translational medicine targeting malignant melanoma

et al. 2019

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Melanoma of the skin is the sixth most common type of cancer in Europe and accounts for 3.4% of all diagnosed cancers. More alarming is the degree of recurrence that occurs with approximately 20% of patients lethally relapsing following treatment. Malignant melanoma is a highly aggressive skin cancer and metastases rapidly extend to the regional lymph nodes (stage 3) and to distal organs (stage 4). Targeted oncotherapy is one of the standard treatment for progressive stage 4 melanoma, and BRAF inhibitors (e.g. vemurafenib, dabrafenib) combined with MEK inhibitor (e.g. trametinib) can effectively counter BRAFV600E-mutated melanomas. Compared to conventional chemotherapy, targeted BRAFV600E inhibition achieves a significantly higher response rate. After a period of cancer control, however, most responsive patients develop resistance to the therapy and lethal progression. The many underlying factors potentially causing resistance to BRAF inhibitors have been extensively studied. Nevertheless, the remaining unsolved clinical questions necessitate alternative research approaches to address the molecular mechanisms underlying metastatic and treatment-resistant melanoma. In broader terms, proteomics can address clinical questions far beyond the reach of genomics, by measuring, i.e. the relative abundance of protein products, post-translational modifications (PTMs), protein localisation, turnover, protein interactions and protein function. More specifically, proteomic analysis of body fluids and tissues in a given medical and clinical setting can aid in the identification of cancer biomarkers and novel therapeutic targets. Achieving this goal requires the development of a robust and reproducible clinical proteomic platform that encompasses automated biobanking of patient samples, tissue sectioning and histological examination, efficient protein extraction, enzymatic digestion, mass spectrometry-based quantitative protein analysis by label-free or labelling technologies and/or enrichment of peptides with specific PTMs. By combining data from, e.g. phosphoproteomics and acetylomics, the protein expression profiles of different melanoma stages can provide a solid framework for understanding the biology and progression of the disease. When complemented by proteogenomics, customised protein sequence databases generated from patient-specific genomic and transcriptomic data aid in interpreting clinical proteomic biomarker data to provide a deeper and more comprehensive molecular characterisation of cellular

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Challenging the heterogeneity of disease presentation in malignant melanoma—impact on patient treatment

Cited by 17 publications

References 52 publications

Automated phosphopeptide enrichment from minute quantities of frozen malignant melanoma tissue

Automated phosphopeptide enrichment from minute quantities of frozen malignant melanoma tissue

Overexpression of microRNA‑21 inhibits the growth and metastasis of melanoma cells by targeting MKK3

Clinical protein science in translational medicine targeting malignant melanoma

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