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Melanoma: Molecular Mechanisms and Therapy

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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 (20 May 2025) | Viewed by 19207

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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; genomic alterations; gene expression alterations; chromosome copy number alterations; array CGH; FISH
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Dear Colleagues,

Melanoma is the most aggressive form of skin cancer, with a very high capacity to metastasize to different organs. The five-year survival rate of patients with early-stage melanoma is over 98%; however, if the primary tumor has spread to distant organs, the survival rate drops to 17%. After introducing several new therapeutic strategies, the prognosis of late-state and metastatic melanomas has improved significantly during the last 10 years. Unfortunately, successful treatment of melanoma patients with distant metastases is still a major therapeutic challenge. The molecular mechanisms that underline the metastatic process into distant organs are only partially understood. After the initial success of either target (e.g., BRAF/MEK inhibitors) or immunotherapies, drug resistance develops in the majority of patients due to various heterogeneous distributions of the molecular alterations. It is imperative to further detail the molecular mechanisms underlying the progression of the disease and the molecular background of the development of drug resistance.

Prof. Dr. Balázs Margit
Guest Editor

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Keywords

melanoma progression
melanoma metastasis molecular background
targeted therapy
immunotherapy
acquired drug resistance
prognostic and predictive markers
therapeutic targets

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Melanoma: Molecular Mechanism and Therapy, 2nd Edition in International Journal of Molecular Sciences

Published Papers (9 papers)

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Research

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22 pages, 6268 KiB

Open AccessArticle

Development and Validation of an Extracellular Matrix Gene Expression Signature for Prognostic Prediction in Patients with Uveal Melanoma

by Alejandro Mejía-García, Carlos A. Orozco, Julius Herzog, Oscar Alarcón-Betancourth, Alexandra Meneses-Torres, Marcela Ramírez, Johanna González, Yina Zambrano, Alba Lucia Combita, Diego A. Bonilla and Seth Frietze

Int. J. Mol. Sci. 2025, 26(9), 4317; https://doi.org/10.3390/ijms26094317 - 1 May 2025

Viewed by 967

Abstract

Uveal melanoma (UVM) is an aggressive cancer with a poor prognosis, particularly in metastatic cases. This study aimed to develop and validate a novel extracellular matrix (ECM) gene expression signature to predict prognosis and stratify patients by risk. ECM-related genes were identified and used to construct a prognostic model through Lasso–Cox regression analysis, leveraging RNA sequencing data from 80 UVM patients in The Cancer Genome Atlas (TCGA). The model was validated using an independent cohort of 63 UVM patients. Survival analyses, immune infiltration profiling, and functional enrichment analyses were conducted to evaluate the biological significance and clinical utility of the signature. The ECM signature stratified patients into high- and low-risk groups with significant differences in survival outcomes. High-risk patients showed elevated expression of MMP1 and MMP12, which are associated with ECM remodeling and immune modulation, alongside increased infiltration of immunosuppressive cells, such as M2 macrophages. Validation confirmed the prognostic value of the signature across cohorts. Functional analyses highlighted the involvement of ECM-related pathways, epithelial–mesenchymal transition, and immune system interactions in tumor progression. This ECM gene expression signature is a robust prognostic tool for UVM, offering insights into tumor biology and immune microenvironment interactions. It holds promise for improving patient stratification and guiding personalized therapeutic strategies. Further research is warranted to explore the functional roles of these genes in UVM progression. Full article

(This article belongs to the Special Issue Melanoma: Molecular Mechanisms and Therapy)

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15 pages, 3219 KiB

Open AccessArticle

High-Glucose-Induced Metabolic and Redox Alterations Are Distinctly Modulated by Various Antidiabetic Agents and Interventions Against FABP5/7, MITF and ANGPTL4 in Melanoma A375 Cells

by Nami Nishikiori, Hiroshi Ohguro, Megumi Watanabe, Megumi Higashide, Toshifumi Ogawa, Masato Furuhashi and Tatsuya Sato

Int. J. Mol. Sci. 2025, 26(3), 1014; https://doi.org/10.3390/ijms26031014 - 24 Jan 2025

Viewed by 1591

Abstract

Hyperglycemia-induced effects on cellular metabolic properties and reactive oxygen species (ROS) generation play pivotal roles in the pathogenesis of malignant melanoma (MM). This study assessed how metabolic states, ROS production, and related gene expression are modulated by antidiabetic agents. The anti-diabetic agents metformin (Met) and imeglimin (Ime), inhibitors of fatty acid-binding proteins 5/7 (MF6) and microphthalmia-associated transcription factor (MITF) (ML329), and siRNA-mediated knockdown of angiopoietin-like protein 4 (ANGPTL4), which affect mitochondrial respiration, ROS production, and related gene expression, were tested in A375 (MM cell line) cells cultured in low (5.5 mM) and high glucose (50 mM) conditions. Cellular metabolic functions were significantly and differently modulated by Met, Ime, MF6, or ML329 and knockdown of ANGPTL4. High glucose significantly enhanced ROS production, which was alleviated by Ime but not by Met. Both MF6 and ML329 reduced ROS levels under both low and high glucose conditions. Knockdown of ANGPTL4 enhanced the change in glucose-dependent ROS production. Gene expression related to mitochondrial respiration and the pathogenesis of MM was significantly modulated by different glucose conditions, antidiabetic agents, MF6, and ML329. These findings suggest that glucose-dependent changes in cellular metabolism and redox status are differently modulated by antidiabetic agents, inhibition of fatty acid-binding proteins or MITF, and ANGPTL4 knockdown in A375 cells. Full article

(This article belongs to the Special Issue Melanoma: Molecular Mechanisms and Therapy)

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23 pages, 4980 KiB

Open AccessArticle

Overcoming Vemurafenib Resistance in Metastatic Melanoma: Targeting Integrins to Improve Treatment Efficacy

by Asiye Busra Boz Er, Helen M. Sheldrake and Mark Sutherland

Int. J. Mol. Sci. 2024, 25(14), 7946; https://doi.org/10.3390/ijms25147946 - 20 Jul 2024

Cited by 2 | Viewed by 2334

Abstract

Metastatic melanoma, a deadly form of skin cancer, often develops resistance to the BRAF inhibitor drug vemurafenib, highlighting the need for understanding the underlying mechanisms of resistance and exploring potential therapeutic strategies targeting integrins and TGF-β signalling. In this study, the role of integrins and TGF-β signalling in vemurafenib resistance in melanoma was investigated, and the potential of combining vemurafenib with cilengitide as a therapeutic strategy was investigated. In this study, it was found that the transcription of PAI1 and p21 was induced by acquired vemurafenib resistance, and ITGA5 levels were increased as a result of this resistance. The transcription of ITGA5 was mediated by the TGF-β pathway in the development of vemurafenib resistance. A synergistic effect on the proliferation of vemurafenib-resistant melanoma cells was observed with the combination therapy of vemurafenib and cilengitide. Additionally, this combination therapy significantly decreased invasion and colony formation in these resistant cells. In conclusion, it is suggested that targeting integrins and TGF-β signalling, specifically ITGA5, ITGB3, PAI1, and p21, may offer promising approaches to overcoming vemurafenib resistance, thereby improving outcomes for metastatic melanoma patients. Full article

(This article belongs to the Special Issue Melanoma: Molecular Mechanisms and Therapy)

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19 pages, 6499 KiB

Open AccessArticle

GLI Transcriptional Targets S100A7 and KRT16 Show Upregulated Expression Patterns in Epidermis Overlying the Tumor Mass in Melanoma Samples

by Matea Kurtović, Nikolina Piteša, Josipa Čonkaš, Helena Hajpek, Majda Vučić, Vesna Musani, Petar Ozretić and Maja Sabol

Int. J. Mol. Sci. 2024, 25(11), 6084; https://doi.org/10.3390/ijms25116084 - 31 May 2024

Viewed by 1700

Abstract

Although not completely understood, the role of the Hedgehog-GLI (HH-GLI) signaling pathway in melanoma and epithelial skin tumors has been reported before. In this study, we confirmed in various melanoma cell line models that keratin 16 (KRT16) and S100 Calcium-Binding Protein A7 (S100A7) are transcriptional targets of GLI Family Zinc Finger (GLI) proteins. Besides their important role in protecting and maintaining the epidermal barrier, keratins are somehow tightly connected with the S100 family of proteins. We found that stronger expression of KRT16 indeed corresponds to stronger expression of S100A7 in our clinical melanoma samples. We also report a trend regarding staining of GLI1, which corresponds to stronger staining of GLI3, KRT16, and S100A7 proteins. The most interesting of our findings is that all the proteins are detected specifically in the epidermis overlying the tumor, but rarely in the tumor itself. The examined proteins were also not detected in the healthy epidermis at the edges of the sample, suggesting that the staining is specific to the epidermis overlaying the tumor mass. Of all proteins, only S100A7 demonstrated a statistically significant trend regarding tumor staging and staining intensity. Results from our clinical samples prove that immune infiltration is an important feature of melanoma. Pigmentophages and tumor-infiltrating lymphocytes (TIL) demonstrate a significant association with tumor stage, while mononuclear cells are equally present in all stages. For S100A7, we found an association between the number of TILs and staining intensity. Considering these new findings presented in our study, we suggest a more detailed examination of the possible role of the S100A7 protein as a biomarker in melanoma. Full article

(This article belongs to the Special Issue Melanoma: Molecular Mechanisms and Therapy)

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15 pages, 2334 KiB

Open AccessArticle

Identification of Plasma Lipid Alterations Associated with Melanoma Metastasis

by István Szász, Viktória Koroknai, Tünde Várvölgyi, László Pál, Sándor Szűcs, Péter Pikó, Gabriella Emri, Eszter Janka, Imre Lőrinc Szabó, Róza Ádány and Margit Balázs

Int. J. Mol. Sci. 2024, 25(8), 4251; https://doi.org/10.3390/ijms25084251 - 11 Apr 2024

Cited by 4 | Viewed by 2043

Abstract

The aim of this study was to apply a state-of-the-art quantitative lipidomic profiling platform to uncover lipid alterations predictive of melanoma progression. Our study included 151 melanoma patients; of these, 83 were without metastasis and 68 with metastases. Plasma samples were analyzed using a targeted Lipidyzer™ platform, covering 13 lipid classes and over 1100 lipid species. Following quality control filters, 802 lipid species were included in the subsequent analyses. Total plasma lipid contents were significantly reduced in patients with metastasis. Specifically, levels of two out of the thirteen lipid classes (free fatty acids (FFAs) and lactosylceramides (LCERs)) were significantly decreased in patients with metastasis. Three lipids (CE(12:0), FFA(24:1), and TAG47:2-FA16:1) were identified as more effective predictors of melanoma metastasis than the well-known markers LDH and S100B. Furthermore, the predictive value substantially improved upon combining the lipid markers. We observed an increase in the cumulative levels of five lysophosphatidylcholines (LPC(16:0); LPC(18:0); LPC(18:1); LPC(18:2); LPC(20:4)), each individually associated with an elevated risk of lymph node metastasis but not cutaneous or distant metastasis. Additionally, seventeen lipid molecules were linked to patient survival, four of which (CE(12:0), CE(14:0), CE(15:0), SM(14:0)) overlapped with the lipid panel predicting metastasis. This study represents the first comprehensive investigation of the plasma lipidome of melanoma patients to date. Our findings suggest that plasma lipid profiles may serve as important biomarkers for predicting clinical outcomes of melanoma patients, including the presence of metastasis, and may also serve as indicators of patient survival. Full article

(This article belongs to the Special Issue Melanoma: Molecular Mechanisms and Therapy)

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Review

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18 pages, 3512 KiB

Open AccessReview

Cancer Stem Cells and the Renin–Angiotensin System in the Tumor Microenvironment of Melanoma: Implications on Current Therapies

by Ethan J. Kilmister and Swee T. Tan

Int. J. Mol. Sci. 2025, 26(3), 1389; https://doi.org/10.3390/ijms26031389 - 6 Feb 2025

Cited by 1 | Viewed by 1636

Abstract

Multiple signaling pathways are dysregulated in melanoma, notably the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways, which can be targeted therapeutically. The high immunogenicity of melanoma has been exploited using checkpoint inhibitors. Whilst targeted therapies and immune checkpoint inhibitors have improved the survival of patients with advanced melanoma, treatment resistance, their side effect profiles, and the prohibitive cost remain a challenge, and the survival outcomes remain suboptimal. Treatment resistance has been attributed to the presence of cancer stem cells (CSCs), a small subpopulation of pluripotent, highly tumorigenic cells proposed to drive cancer progression, recurrence, metastasis, and treatment resistance. CSCs reside within the tumor microenvironment (TME) regulated by the immune system, and the paracrine renin–angiotensin system, which is expressed in many cancer types, including melanoma. This narrative review discusses the role of CSCs and the paracrine renin–angiotensin system in the melanoma TME, and its implications on the current treatment of advanced melanoma with targeted therapy and immune checkpoint blockers. It also highlights the regulation of the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways by the renin–angiotensin system via pro-renin receptors, and how this may relate to CSCs and treatment resistance, underscoring the potential for improving the efficacy of targeted therapy and immunotherapy by concurrently modulating the renin–angiotensin system. Full article

(This article belongs to the Special Issue Melanoma: Molecular Mechanisms and Therapy)

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11 pages, 6363 KiB

Open AccessReview

Advances in Tumor-Infiltrating Lymphocyte (TIL) as a Prognostic Factor and for Treating Invasive Cutaneous Melanoma

by Gabriel Alves Freiria de Oliveira, Daniel Arcuschin de Oliveira, Melissa Yoshimi Sakamoto Maeda Nisimoto, Rafael Rubinho, Heitor Carvalho Gomes, Luciana Cavalheiro Marti and Renato Santos de Oliveira Filho

Int. J. Mol. Sci. 2024, 25(23), 12596; https://doi.org/10.3390/ijms252312596 - 23 Nov 2024

Viewed by 1639

Abstract

Invasive cutaneous melanoma is responsible for about 5% of skin tumors yet is liable for nearly 70% of skin cancer-related deaths. Despite notable advancements over the past decade, including immunotherapies and targeted treatments, more than half of invasive melanoma patients ultimately succumb to the disease due to therapeutic resistance. To overcome this obstacle, strategies such as combining immunotherapies with targeted drugs or adding epigenetic therapies have been investigated. Tumor-infiltrating lymphocytes (TILs) therapy has emerged as a promising option for patients whose disease continues to progress despite standard treatments. This article aims to introduce TIL therapy and review recent outcomes in melanoma prognosis in its application for melanoma management. Full article

(This article belongs to the Special Issue Melanoma: Molecular Mechanisms and Therapy)

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28 pages, 2933 KiB

Open AccessReview

Current Insights into the Role of UV Radiation-Induced Oxidative Stress in Melanoma Pathogenesis

by Ernest Gieniusz, Elżbieta Skrzydlewska and Wojciech Łuczaj

Int. J. Mol. Sci. 2024, 25(21), 11651; https://doi.org/10.3390/ijms252111651 - 30 Oct 2024

Cited by 4 | Viewed by 3396

Abstract

Cutaneous melanoma accounts for the majority of skin cancer-related deaths, and its incidence increases each year. The growing number of melanoma cases, especially in advanced stages, poses a significant socio-medical challenge throughout the world. Extensive research on melanoma pathogenesis identifies UV radiation as the most important factor in melanocytic transformation. Oxidative effects of UV irradiation exert their influence on melanoma pathogenesis primarily through modification of nucleic acids, proteins, and lipids, further disrupting cellular signaling and cell cycle regulation. Its effects extend beyond melanocytes, leading to immunosuppression in the exposed skin tissue, which consequently creates conditions for immune surveillance evasion and further progression. In this review, we focus on the specific molecular changes observed in the UV-dependent oxidative stress environment and their biological consequences in the course of the disease, which have not been considered in previous reviews on melanoma. Nonetheless, data show that the exact role of oxidative stress in melanoma initiation and progression remains unclear, as it affects cancerous cells differently depending on the specific context. A better understanding of the pathophysiological basis of melanoma development holds promise for identifying potential targets, which could lead to effective melanoma prevention strategies. Full article

(This article belongs to the Special Issue Melanoma: Molecular Mechanisms and Therapy)

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26 pages, 1239 KiB

Open AccessReview

Amelanotic Melanoma—Biochemical and Molecular Induction Pathways

by Piotr Misiąg, Klaudia Molik, Monika Kisielewska, Paulina Typek, Izabela Skowron, Anna Karwowska, Jacek Kuźnicki, Aleksandra Wojno, Marcin Ekiert and Anna Choromańska

Int. J. Mol. Sci. 2024, 25(21), 11502; https://doi.org/10.3390/ijms252111502 - 26 Oct 2024

Cited by 4 | Viewed by 2911

Abstract

Amelanotic melanoma (AM) is a subtype of hypomelanotic or completely amelanotic melanoma. AM is a rare subtype of melanoma that exhibits a higher recurrence rate and aggressiveness as well as worse surveillance than typical melanoma. AM shows a dysregulation of melanin production, cell cycle control, and apoptosis pathways. Knowing these pathways has an application in medicine due to targeted therapies based on the inhibiting elements of the abovementioned pathways. Therefore, we summarized and discussed AM biochemical and molecular induction pathways and personalized medicine approaches, clinical management, and future directions due to the fact that AM is relatively rare. AM is commonly misdiagnosed. Hence, the role of biomarkers is becoming significant. Nonetheless, there is a shortage of biomarkers specific to AM. BRAF, NRAS, and c-KIT genes are the main targets of therapy. However, the role of BRAF and KIT in AM varied among studies. BRAF inhibitors combined with MAK inhibitors demonstrate better results. Immune checkpoint inhibitors targeting CTLA-4 combined with a programmed death receptor 1 (PD-1) show better outcomes than separately. Fecal microbiota transplantation may overcome resistance to immune checkpoint therapy of AM. Immune-modulatory vaccines against indoleamine 2,3-dioxygenase (IDO) and PD ligand (PD-L1) combined with nivolumab may be efficient in melanoma treatment. Full article

(This article belongs to the Special Issue Melanoma: Molecular Mechanisms and Therapy)

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