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Molecular Biology of Melanoma 2.0

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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 (30 September 2023) | Viewed by 13603

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Prof. Dr. Balázs Margit

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Guest Editor

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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Special Issue Information

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. Balázs Margit
Guest Editor

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Keywords

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

Published Papers (6 papers)

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Research

13 pages, 2408 KiB

Open AccessArticle

Gene Expression Changes in Cytokine and Chemokine Receptors in Association with Melanoma Liver Metastasis

by Viktória Koroknai, István Szász and Margit Balázs

Int. J. Mol. Sci. 2023, 24(10), 8901; https://doi.org/10.3390/ijms24108901 - 17 May 2023

Cited by 2 | Viewed by 1562

Abstract

Cytokines and chemokines (chemotactic cytokines) are soluble extracellular proteins that bind to specific receptors and play an integral role in the cell-to-cell signaling network. In addition, they can promote the homing of cancer cells into different organs. We investigated the potential relationship between human hepatic sinusoidal endothelial cells (HHSECs) and several melanoma cell lines for the expression of chemokine and cytokine ligands and receptor expression during the invasion of melanoma cells. In order to identify differences in gene expression related to invasion, we selected invasive and non-invasive subpopulations of cells after co-culturing with HHSECs and identified the gene expression patterns of 88 chemokine/cytokine receptors in all cell lines. Cell lines with stable invasiveness and cell lines with increased invasiveness displayed distinct profiles of receptor genes. Cell lines with increased invasive capacity after culturing with conditioned medium showed a set of receptor genes (CXCR1, IL1RL1, IL1RN, IL3RA, IL8RA, IL11RA, IL15RA, IL17RC, and IL17RD) with significantly different expressions. It is very important to emphasize that we detected significantly higher IL11RA gene expression in primary melanoma tissues with liver metastasis as well, compared to those without metastasis. In addition, we assessed protein expression in endothelial cells before and after co-culturing them with melanoma cell lines by applying chemokine and cytokine proteome arrays. This analysis revealed 15 differentially expressed proteins (including CD31, VCAM-1, ANGPT2, CXCL8, and CCL20) in the hepatic endothelial cells after co-culture with melanoma cells. Our results clearly indicate the interaction between liver endothelial and melanoma cells. Furthermore, we assume that overexpression of the IL11RA gene may play a key role in organ-specific metastasis of primary melanoma cells to the liver. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma 2.0)

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14 pages, 1246 KiB

Open AccessArticle

Netrin-1 Stimulates Migration of Neogenin Expressing Aggressive Melanoma Cells

by Gustavo Untiveros, Aleksandr Raskind, Laura Linares, Alessandro Dotti and Luigi Strizzi

Int. J. Mol. Sci. 2022, 23(21), 12751; https://doi.org/10.3390/ijms232112751 - 22 Oct 2022

Cited by 3 | Viewed by 1737

Abstract

Netrin-1 is a neural guidance factor that regulates migration and positioning of neural crest-derived cells during embryonic development. Depending on the type of Netrin-1 receptor expression, cells are either attracted or repulsed by Netrin-1. Postnatal expression of Netrin-1 is detected in brain, colon, liver, and kidney, which are common sites of cancer metastasis, including melanoma. Thus, understanding the dynamics between Netrin-1 and its receptors could explain the attraction of melanoma towards these Netrin-1-expressing tissues. Here, we investigate whether the Netrin-1-attractive receptor Neogenin can affect migration of melanoma cells towards a Netrin-1 source. Results from Western blot (WB) analysis show higher expression of Neogenin in aggressive compared to non-aggressive melanoma cells. Cell migration experiments show increased migration of Neogenin-expressing aggressive melanoma cells towards exogenous, soluble recombinant human Netrin-1 and towards a Netrin-1-expressing cell line. Furthermore, WB reveals ERK1/2 activation and increased N-cadherin expression in Neogenin-expressing aggressive melanoma cells treated with rhNetrin-1. Moreover, treatment with anti-Neogenin blocking antibody caused decreased migration towards Netrin-1-expressing cells and reduced ERK1/2 activity in Neogenin-expressing aggressive melanoma cells. These results suggest Neogenin may play a role during migration of melanoma cells towards Netrin-1 via ERK1/2 signaling. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma 2.0)

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19 pages, 4729 KiB

Open AccessArticle

Characterization of Vemurafenib-Resistant Melanoma Cell Lines Reveals Novel Hallmarks of Targeted Therapy Resistance

by Martina Radić, Ignacija Vlašić, Maja Jazvinšćak Jembrek, Anđela Horvat, Ana Tadijan, Maja Sabol, Marko Dužević, Maja Herak Bosnar and Neda Slade

Int. J. Mol. Sci. 2022, 23(17), 9910; https://doi.org/10.3390/ijms23179910 - 31 Aug 2022

Cited by 10 | Viewed by 2971

Abstract

Regardless of the significant improvements in treatment of melanoma, the majority of patients develop resistance whose mechanisms are still not completely understood. Hence, we generated and characterized two melanoma-derived cell lines, primary WM793B and metastatic A375M, with acquired resistance to the RAF inhibitor vemurafenib. The morphology of the resistant primary WM793B melanoma cells showed EMT-like features and exhibited a hybrid phenotype with both epithelial and mesenchymal characteristics. Surprisingly, the vemurafenib-resistant melanoma cells showed a decreased migration ability but also displayed a tendency to collective migration. Signaling pathway analysis revealed the reactivation of MAPK and the activation of the PI3K/AKT pathway depending on the vemurafenib-resistant cell line. The acquired resistance to vemurafenib caused resistance to chemotherapy in primary WM793B melanoma cells. Furthermore, the cell-cycle analysis and altered levels of cell-cycle regulators revealed that resistant cells likely transiently enter into cell cycle arrest at the G0/G1 phase and gain slow-cycling cell features. A decreased level of NME1 and NME2 metastasis suppressor proteins were found in WM793B-resistant primary melanoma, which is possibly the result of vemurafenib-acquired resistance and is one of the causes of increased PI3K/AKT signaling. Further studies are needed to reveal the vemurafenib-dependent negative regulators of NME proteins, their role in PI3K/AKT signaling, and their influence on vemurafenib-resistant melanoma cell characteristics. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma 2.0)

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16 pages, 581 KiB

Open AccessArticle

Identification of a Tumor Cell Associated Type I IFN Resistance Gene Expression Signature of Human Melanoma, the Components of Which Have a Predictive Potential for Immunotherapy

by Andrea Ladányi, Erzsébet Rásó, Tamás Barbai, Laura Vízkeleti, László G. Puskás, Szonja A. Kovács, Balázs Győrffy and József Tímár

Int. J. Mol. Sci. 2022, 23(5), 2704; https://doi.org/10.3390/ijms23052704 - 28 Feb 2022

Cited by 3 | Viewed by 2109

Abstract

We developed a human melanoma model using the HT168-M1 cell line to induce IFN-α2 resistance in vitro (HT168-M1res), which was proven to be maintained in vivo in SCID mice. Comparing the mRNA profile of in vitro cultured HT168-M1res cells to its sensitive counterpart, we found 79 differentially expressed genes (DEGs). We found that only a 13-gene core of the DEGs was stable in vitro and only a 4-gene core was stable in vivo. Using an in silico cohort of IFN-treated melanoma tissues, we validated a differentially expressed 9-gene core of the DEGs. Furthermore, using an in silico cohort of immune checkpoint inhibitor (ICI)-treated melanoma tissues, we tested the predictive power of the DEGs for the response rate. Analysis of the top four upregulated and top four downregulated genes of the DEGs identified WFDC1, EFNA3, DDX10, and PTBP1 as predictive genes, and analysis of the “stable” genes of DEGs for predictive potential of ICI response revealed another 13 genes, out of which CDCA4, SOX4, DEK, and HSPA1B were identified as IFN-regulated genes. Interestingly, the IFN treatment associated genes and the ICI-therapy predictive genes overlapped by three genes: WFDC1, BCAN, and MT2A, suggesting a connection between the two biological processes. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma 2.0)

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10 pages, 1384 KiB

Open AccessArticle

Cytokine and Chemokine Receptor Patterns of Human Malignant Melanoma Cell Lines

by Viktoria Koroknai, István Szász, Krisztina Jámbor and Margit Balázs

Int. J. Mol. Sci. 2022, 23(5), 2644; https://doi.org/10.3390/ijms23052644 - 28 Feb 2022

Cited by 4 | Viewed by 1844

Abstract

Cytokine and chemokine receptors can promote tumor progression, invasion, and metastasis development by inducing different intracellular signaling pathways. The aim of this study was to determine the cytokine and chemokine receptor gene expression patterns in human melanoma cell lines. We found a large set of cytokine and chemokine receptor genes that were significantly differentially expressed between melanoma cell lines that originated from different subtypes of primary melanomas as well as cell lines that originated from melanoma metastases. The relative expressions of two receptor genes (CCR2 and TNFRSF11B) were positively correlated with the invasive potential of the cell lines, whereas a negative correlation was observed for the TNFRSF14 gene expression. We also found a small set of receptor genes that exhibited a significantly decreased expression in association with a BRAF^V600E mutation. Based on our results, we assume that the analyzed cytokine and chemokine receptor collection may provide potential to distinguish the different subtypes of melanomas, helping us to understand the biological behavior of BRAF^V600E-mutated melanoma cells. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma 2.0)

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15 pages, 3497 KiB

Open AccessArticle

Extracellular Matrix Remodeling by Fibroblast-MMP14 Regulates Melanoma Growth

by Elke Pach, Maike Kümper, Julia E. Fromme, Jan Zamek, Fabian Metzen, Manuel Koch, Cornelia Mauch and Paola Zigrino

Int. J. Mol. Sci. 2021, 22(22), 12276; https://doi.org/10.3390/ijms222212276 - 12 Nov 2021

Cited by 14 | Viewed by 2533

Abstract

Maintaining a balanced state in remodeling the extracellular matrix is crucial for tissue homeostasis, and this process is altered during skin cancer progression. In melanoma, several proteolytic enzymes are expressed in a time and compartmentalized manner to support tumor progression by generating a permissive environment. One of these proteases is the matrix metalloproteinase 14 (MMP14). We could previously show that deletion of MMP14 in dermal fibroblasts results in the generation of a fibrotic-like skin in which melanoma growth is impaired. That was primarily due to collagen I accumulation due to lack of the collagenolytic activity of MMP14. However, as well as collagen I processing, MMP14 can also process several extracellular matrices. We investigated extracellular matrix alterations occurring in the MMP14-deleted fibroblasts that can contribute to the modulation of melanoma growth. The matrix deposited by cultured MMP14-deleted fibroblast displayed an antiproliferative and anti-migratory effect on melanoma cells in vitro. Analysis of the secreted and deposited-decellularized fibroblast’s matrix identified a few altered proteins, among which the most significantly changed was collagen XIV. This collagen was increased because of post-translational events, while de novo synthesis was unchanged. Collagen XIV as a substrate was not pro-proliferative, pro-migratory, or adhesive, suggesting a negative regulatory role on melanoma cells. Consistent with that, increasing collagen XIV concentration in wild-type fibroblast-matrix led to reduced melanoma proliferation, migration, and adhesion. In support of its anti-tumor activity, enhanced accumulation of collagen XIV was detected in peritumoral areas of melanoma grown in mice with the fibroblast’s deletion of MMP14. In advanced human melanoma samples, we detected reduced expression of collagen XIV compared to benign nevi, which showed a robust expression of this molecule around melanocytic nests. This study shows that loss of fibroblast-MMP14 affects melanoma growth through altering the peritumoral extracellular matrix (ECM) composition, with collagen XIV being a modulator of melanoma progression and a new proteolytic substrate to MMP14. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma 2.0)

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