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Molecular Biology of Melanoma

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (29 February 2020) | Viewed by 45658

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Prof. Dr. Balázs Margit

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Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Interests: human malignant melanoma; metastatic progression; genomic alterations; gene expression alterations; chromosome copy number alterations; array CGH; FISH
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Dear Colleagues,

Cutaneous melanoma is one of the most invasive and metastatic human cancers, and accounts for the majority of skin cancer deaths despite comprising less than 5% of all cutaneous malignancies [1]. Although local excision for early-stage primary melanoma offers the best chance of cure, recent advances in molecular genetics and genomics have revolutionized the management and treatment of late-stage and metastatic melanomas, leading to significant improvements in clinical outcomes [2]. Approximately 40%–50% of melanomas harbour an activating mutation in the BRAF oncogene, which constitutively activates the mitogen-activated protein kinase (MAPK) pathway. The targeted inhibition of the mutant BRAF gene is one of the most promising therapeutic approaches for patients with unresectable or metastatic melanoma. BRAF inhibitors have high response rates amongst patients with advantaged state melanomas. Unfortunately, despite the 6–8 month median progression-free survival, most patients develop resistance and experience tumour re-growth. However, the recent successes of single-agent and combination therapies are promising; improving the currently existing classification schemes of patients for the appropriate treatment as well as understanding the mechanism of therapeutic resistance are still crucial goals. Chemoresistance as well as a high metastatic potential are supposed to be in association with the fact that melanocytes are derived from highly motile neural crest precursors [3]. Different invasion strategies can be used by melanoma cells, depending on varying environmental effects, to invade the surrounding and distant tissues. While new agents are already used to successfully treat malignant melanomas, a more personalized approach incorporating genomic, proteomic, and immunologic data are needed for successful therapeutic decisions [4].

Clin Exp Metastasis. 2018 Aug;35(5-6):379-391.
Br J Surg. 2018 Jan;105(2):e31-e47.
Cancer Metastasis Rev. 2017 Mar;36(1):7-21.
Expert Opin Pharmacother. 2017 Apr;18(5):487-495.

Prof. Dr. Margit Balázs
Guest Editors

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Keywords

melanoma
cutaneous
genomic alterations
invasion related molecular markers
driver genes
metastasis
personalized therapies
BRAF inhibitors
immunotherapy

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Diagnostics and Therapeutics of Melanoma in Biomedicines (14 articles)

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16 pages, 3330 KiB

Open AccessArticle

Exploring the Potential Use of a PBMC-Based Functional Assay to Identify Predictive Biomarkers for Anti-PD-1 Immunotherapy

by Silvia M. Bacot, Taylor A. Harper, Rebecca L. Matthews, Christie Jane Fennell, Adovi Akue, Mark A. KuKuruga, Shiowjen Lee, Tao Wang and Gerald M. Feldman

Int. J. Mol. Sci. 2020, 21(23), 9023; https://doi.org/10.3390/ijms21239023 - 27 Nov 2020

Cited by 18 | Viewed by 4876

Abstract

The absence of reliable, robust, and non-invasive biomarkers for anti- Programmed cell death protein 1 (PD-1) immunotherapy is an urgent unmet medical need for the treatment of cancer patients. No predictive biomarkers have been established based on the direct assessment of T cell functions, the primary mechanism of action of anti-PD-1 therapy. In this study, we established a model system to test T cell functions modulated by Nivolumab using anti-CD3 monoclonal antibody (mAb)-stimulated peripheral blood mononuclear cells (PBMCs), and characterized T cell functions primarily based on the knowledge gained from retrospective observations of patients treated with anti-PD-1 immunotherapy. During a comprehensive cytokine profile assessment to identify potential biomarkers, we found that Nivolumab increases expression of T helper type 1 (Th1) associated cytokines such as interferon-γ (IFN-γ) and interleukin-2 (IL-2) in a subset of donors. Furthermore, Nivolumab increases production of Th2, Th9, and Th17 associated cytokines, as well as many proinflammatory cytokines such as IL-6 in a subset of donors. Conversely, Nivolumab treatment has no impact on T cell proliferation, expression of CD25, CD69, or Granzyme B, and only modestly increases in the expansion of regulatory T cells. Our results suggest that assessment of cytokine production using a simple PBMC-based T cell functional assay could be used as a potential predictive marker for anti-PD-1 immunotherapy. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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28 pages, 11591 KiB

Open AccessArticle

Knockout of ACTB and ACTG1 with CRISPR/Cas9(D10A) Technique Shows that Non-Muscle β and γ Actin Are Not Equal in Relation to Human Melanoma Cells’ Motility and Focal Adhesion Formation

by Natalia Malek, Ewa Mrówczyńska, Aleksandra Michrowska, Ewa Mazurkiewicz, Iuliia Pavlyk and Antonina Joanna Mazur

Int. J. Mol. Sci. 2020, 21(8), 2746; https://doi.org/10.3390/ijms21082746 - 15 Apr 2020

Cited by 20 | Viewed by 5985

Abstract

Non-muscle actins have been studied for many decades; however, the reason for the existence of both isoforms is still unclear. Here we show, for the first time, a successful inactivation of the ACTB (CRISPR clones with inactivated ACTB, CR-ACTB) and ACTG1 (CRISPR clones with inactivated ACTG1, CR-ACTG1) genes in human melanoma cells (A375) via the RNA-guided D10A mutated Cas9 nuclease gene editing [CRISPR/Cas9(D10A)] technique. This approach allowed us to evaluate how melanoma cell motility was impacted by the lack of either β actin coded by ACTB or γ actin coded by ACTG1. First, we observed different distributions of β and γ actin in the cells, and the absence of one actin isoform was compensated for via increased expression of the other isoform. Moreover, we noted that γ actin knockout had more severe consequences on cell migration and invasion than β actin knockout. Next, we observed that the formation rate of bundled stress fibers in CR-ACTG1 cells was increased, but lamellipodial activity in these cells was impaired, compared to controls. Finally, we discovered that the formation rate of focal adhesions (FAs) and, subsequently, FA-dependent signaling were altered in both the CR-ACTB and CR-ACTG1 clones; however, a more detrimental effect was observed for γ actin-deficient cells. Our research shows that both non-muscle actins play distinctive roles in melanoma cells’ FA formation and motility. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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31 pages, 5937 KiB

Open AccessArticle

Human Melanoma-Cell Metabolic Profiling: Identification of Novel Biomarkers Indicating Metastasis

by Mariangela Kosmopoulou, Aikaterini F. Giannopoulou, Aikaterini Iliou, Dimitra Benaki, Aristeidis Panagiotakis, Athanassios D. Velentzas, Eumorphia G. Konstantakou, Issidora S. Papassideri, Emmanuel Mikros, Dimitrios J. Stravopodis and Evagelos Gikas

Int. J. Mol. Sci. 2020, 21(7), 2436; https://doi.org/10.3390/ijms21072436 - 31 Mar 2020

Cited by 20 | Viewed by 4548

Abstract

Melanoma is the most aggressive type of skin cancer, leading to metabolic rewiring and enhancement of metastatic transformation. Efforts to improve its early and accurate diagnosis are largely based on preclinical models and especially cell lines. Hence, we herein present a combinational Nuclear Magnetic Resonance (NMR)- and Ultra High Performance Liquid Chromatography-High-Resolution Tandem Mass Spectrometry (UHPLC-HRMS/MS)-mediated untargeted metabolomic profiling of melanoma cells, to landscape metabolic alterations likely controlling metastasis. The cell lines WM115 and WM2664, which belong to the same patient, were examined, with WM115 being derived from a primary, pre-metastatic, tumor and WM2664 clonally expanded from lymph-node metastases. Metabolite samples were analyzed using NMR and UHPLC-HRMS. Multivariate statistical analysis of high resolution NMR and MS (positive and negative ionization) results was performed by Principal Component Analysis (PCA), Partial Least Squares-Discriminant Analysis (PLS-DA) and Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA), while metastasis-related biomarkers were determined on the basis of VIP lists, S-plots and Student’s t-tests. Receiver Operating Characteristic (ROC) curves of NMR and MS data revealed significantly differentiated metabolite profiles for each cell line, with WM115 being mainly characterized by upregulated levels of phosphocholine, choline, guanosine and inosine. Interestingly, WM2664 showed notably increased contents of hypoxanthine, myo-inositol, glutamic acid, organic acids, purines, pyrimidines, AMP, ADP, ATP and UDP(s), thus indicating the critical roles of purine, pyrimidine and amino acid metabolism during human melanoma metastasis. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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15 pages, 3574 KiB

Open AccessArticle

The Antitumor Effect of Lipophilic Bisphosphonate BPH1222 in Melanoma Models: The Role of the PI3K/Akt Pathway and the Small G Protein Rheb

by Dominika Rittler, Marcell Baranyi, Eszter Molnár, Tamás Garay, István Jalsovszky, Imre Károly Varga, Luca Hegedűs, Clemens Aigner, József Tóvári, József Tímár and Balázs Hegedűs

Int. J. Mol. Sci. 2019, 20(19), 4917; https://doi.org/10.3390/ijms20194917 - 3 Oct 2019

Cited by 13 | Viewed by 3274

Abstract

Malignant melanoma is one of the most metastatic cancer types, and despite recent success with novel treatment strategies, there is still a group of patients who do not respond to any therapies. Earlier, the prenylation inhibitor hydrophilic bisphosphonate zoledronic acid (ZA) was found to inhibit melanoma growth in vitro, but only a weaker effect was observed in vivo due to its hydrophilic properties. Recently, lipophilic bisphosphonates (such as BPH1222) were developed. Accordingly, for the first time, we compared the effect of BPH1222 to ZA in eight melanoma lines using viability, cell-cycle, clonogenic and spheroid assays, videomicroscopy, immunoblot, and xenograft experiments. Based on 2D and spheroid assays, the majority of cell lines were more sensitive to BPH. The activation of Akt and S6 proteins, but not Erk, was inhibited by BPH. Additionally, BPH had a stronger apoptotic effect than ZA, and the changes of Rheb showed a correlation with apoptosis. In vitro, only M24met cells were more sensitive to ZA than to BPH; however, in vivo growth of M24met was inhibited more strongly by BPH. Here, we present that lipophilic BPH is more effective on melanoma cells than ZA and identify the PI3K pathway, particularly Rheb as an important mediator of growth inhibition. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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13 pages, 1667 KiB

Open AccessArticle

Long-Term Vemurafenib Exposure Induced Alterations of Cell Phenotypes in Melanoma: Increased Cell Migration and Its Association with EGFR Expression

by Eszter Molnár, Tamás Garay, Marco Donia, Marcell Baranyi, Dominika Rittler, Walter Berger, József Tímár, Michael Grusch and Balázs Hegedűs

Int. J. Mol. Sci. 2019, 20(18), 4484; https://doi.org/10.3390/ijms20184484 - 11 Sep 2019

Cited by 22 | Viewed by 3485

Abstract

Acquired resistance during BRAF inhibitor therapy remains a major challenge for melanoma treatment. Accordingly, we evaluated the phenotypical and molecular changes of isogeneic human V600E BRAF-mutant melanoma cell line pairs pre- and post-treatment with vemurafenib. Three treatment naïve lines were subjected to in vitro long-term vemurafenib treatment while three pairs were pre- and post-treatment patient-derived lines. Molecular and phenotypical changes were assessed by Sulforhodamine-B (SRB) assay, quantitative RT-PCR (q-RT-PCR), immunoblot, and time-lapse microscopy. We found that five out of six post-treatment cells had higher migration activity than pretreatment cells. However, no unequivocal correlation between increased migration and classic epithelial–mesenchymal transition (EMT) markers could be identified. In fast migrating cells, the microphthalmia-associated transcription factor (MITF) and epidermal growth factor receptor (EGFR) mRNA levels were considerably lower and significantly higher, respectively. Interestingly, high EGFR expression was associated with elevated migration but not with proliferation. Cells with high EGFR expression showed significantly decreased sensitivity to vemurafenib treatment, and had higher Erk activation and FRA-1 expression. Importantly, melanoma cells with higher EGFR expression were more resistant to the EGFR inhibitor erlotinib treatment than cells with lower expression, with respect to both proliferation and migration inhibition. Finally, EGFR-high melanoma cells were characterized by higher PD-L1 expression, which might in turn indicate that immunotherapy may be an effective approach in these cases. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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20 pages, 3993 KiB

Open AccessArticle

Physiologically Relevant Oxygen Concentration (6% O₂) as an Important Component of the Microenvironment Impacting Melanoma Phenotype and Melanoma Response to Targeted Therapeutics In Vitro

by Marta Osrodek, Mariusz L. Hartman and Malgorzata Czyz

Int. J. Mol. Sci. 2019, 20(17), 4203; https://doi.org/10.3390/ijms20174203 - 27 Aug 2019

Cited by 18 | Viewed by 4198

Abstract

Cancer cell phenotype largely depends on oxygen availability. The atmospheric oxygen concentration (21%) used in in vitro studies is much higher than in any human tissue. Using well-characterized patient-derived melanoma cell lines, we compared: (i) activities of several signaling pathways, and (ii) the effects of vemurafenib and trametinib in hyperoxia (21% O₂), normoxia (6% O₂) and hypoxia (1% O₂). A high plasticity of melanoma cells in response to changes in oxygen supplementation and drug treatment was observed, and the transcriptional reprograming and phenotypic changes varied between cell lines. Normoxia enhanced the expression of vascular endothelial growth factor (VEGF), glucose metabolism/transport-related genes, and changed percentages of NGFR- and MITF-positive cells in cell line-dependent manner. Increased protein stability might be responsible for high PGC1α level in MITF^low melanoma cells. Vemurafenib and trametinib while targeting the activity of MAPK/ERK pathway irrespective of oxygen concentration, were less effective in normoxia than hyperoxia in reducing levels of VEGF, PGC1α, SLC7A11 and Ki-67-positive cells in cell line-dependent manner. In conclusion, in vitro studies performed in atmospheric oxygen concentration provide different information on melanoma cell phenotype and response to drugs than performed in normoxia, which might partially explain the discrepancies between results obtained in vitro and in clinical settings. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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34 pages, 27533 KiB

Open AccessArticle

Gene-Specific Intron Retention Serves as Molecular Signature that Distinguishes Melanoma from Non-Melanoma Cancer Cells in Greek Patients

by Aikaterini F. Giannopoulou, Eumorphia G. Konstantakou, Athanassios D. Velentzas, Socratis N. Avgeris, Margaritis Avgeris, Nikos C. Papandreou, Ilianna Zoi, Vicky Filippa, Stamatia Katarachia, Antonis D. Lampidonis, Anastasia Prombona, Popi Syntichaki, Christina Piperi, Efthimia K. Basdra, Vassiliki Iconomidou, Evangelia Papadavid, Ema Anastasiadou, Issidora S. Papassideri, Athanasios G. Papavassiliou, Gerassimos E. Voutsinas, Andreas Scorilas and Dimitrios J. Stravopodis Show full author list Hide full author list

Int. J. Mol. Sci. 2019, 20(4), 937; https://doi.org/10.3390/ijms20040937 - 21 Feb 2019

Cited by 9 | Viewed by 4827

Abstract

Background: Skin cancer represents the most common human malignancy, and it includes BCC, SCC, and melanoma. Since melanoma is one of the most aggressive types of cancer, we have herein attempted to develop a gene-specific intron retention signature that can distinguish BCC and SCC from melanoma biopsy tumors. Methods: Intron retention events were examined through RT-sqPCR protocols, using total RNA preparations derived from BCC, SCC, and melanoma Greek biopsy specimens. Intron-hosted miRNA species and their target transcripts were predicted via the miRbase and miRDB bioinformatics platforms, respectively. Ιntronic ORFs were recognized through the ORF Finder application. Generation and visualization of protein interactomes were achieved by the IntAct and Cytoscape softwares, while tertiary protein structures were produced by using the I-TASSER online server. Results: c-MYC and Sestrin-1 genes proved to undergo intron retention specifically in melanoma. Interaction maps of proteins encoded by genes being potentially targeted by retained intron-accommodated miRNAs were generated and SRPX2 was additionally delivered to our melanoma-specific signature. Novel ORFs were identified in MCT4 and Sestrin-1 introns, with potentially critical roles in melanoma development. Conclusions: The property of c-MYC, Sestrin-1, and SRPX2 genes to retain specific introns could be clinically used to molecularly differentiate non-melanoma from melanoma tumors. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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Review

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27 pages, 1200 KiB

Open AccessReview

Current Molecular Markers of Melanoma and Treatment Targets

by Kevin Yang, Allen S.W. Oak, Radomir M. Slominski, Anna A. Brożyna and Andrzej T. Slominski

Int. J. Mol. Sci. 2020, 21(10), 3535; https://doi.org/10.3390/ijms21103535 - 16 May 2020

Cited by 51 | Viewed by 6979

Abstract

Melanoma is a deadly skin cancer that becomes especially difficult to treat after it metastasizes. Timely identification of melanoma is critical for effective therapy, but histopathologic diagnosis can frequently pose a significant challenge to this goal. Therefore, auxiliary diagnostic tools are imperative to facilitating prompt recognition of malignant lesions. Melanoma develops as result of a number of genetic mutations, with UV radiation often acting as a mutagenic risk factor. Novel methods of genetic testing have improved detection of these molecular alterations, which subsequently revealed important information for diagnosis and prognosis. Rapid detection of genetic alterations is also significant for choosing appropriate treatment and developing targeted therapies for melanoma. This review will delve into the understanding of various mutations and the implications they may pose for clinical decision making. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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28 pages, 1467 KiB

Open AccessReview

The miRNAs Role in Melanoma and in Its Resistance to Therapy

by Francesca Varrone and Emilia Caputo

Int. J. Mol. Sci. 2020, 21(3), 878; https://doi.org/10.3390/ijms21030878 - 29 Jan 2020

Cited by 59 | Viewed by 6514

Abstract

Melanoma is the less common but the most malignant skin cancer. Since the survival rate of melanoma metastasis is about 10–15%, many different studies have been carried out in order to find a more effective treatment. Although the development of target-based therapies and immunotherapeutic strategies has improved chances for patient survival, melanoma treatment still remains a big challenge for oncologists. Here, we collect recent data about the emerging role of melanoma-associated microRNAs (miRNAs) currently available treatments, and their involvement in drug resistance. We also reviewed miRNAs as prognostic factors, because of their chemical stability and resistance to RNase activity, in melanoma progression. Moreover, despite miRNAs being considered small conserved regulators with the limitation of target specificity, we outline the dual role of melanoma-associated miRNAs, as oncogenic and/or tumor suppressive factors, compared to other tumors. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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