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Melanoma: From Molecular Mechanisms to Therapeutic Opportunities
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Melanoma: From Molecular Mechanisms to Therapeutic Opportunities

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 24418

Special Issue Editors

Dr. Dean S. Rosenthal

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University School of Medicine, Washington, DC, USA
Interests: apoptosis; genotoxicity; DNA damage; skin biology; wound healing; melanoma; cancer
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Cynthia Simbulan-Rosenthal

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University School of Medicine, Washington, DC, USA
Interests: apoptosis; genotoxicity; skin biology; melanoma; cancer; cell proliferation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Malignant melanoma remains a formidable challenge, with ~106,110 new cases and ~7,180 deaths in the United States in 2021. Drug and immune resistance, together with invasion and metastasis, determine tumor progression, and, ultimately, patient survival. With the highest mortality rate among skin cancers, cutaneous melanoma is associated with driver mutations in MAPK and other signaling pathways, including RAS/PI3K/AKT, p16INK4a/CDK4/RB, WNT, and p53. Activating mutations are primarily in V600 or K601 of BRAF (50% of melanomas), Q61 of NRAS (>20%), and LOF mutations in NF1 (10%).  Although combinations of targeted kinase inhibitors for BRAF and MEK, combined with immune checkpoint inhibitors, have improved progression-free and overall survival of melanoma patients, ~ 75% of melanomas recur after BRAF copy number gains, alternative splicing, MEK1/2, and NRAS gain-of-function mutations; 20% of BRAFi-resistant melanomas upregulate compensatory PI3K/AKT survival pathways. Although treatment for recalcitrant NRAS-mutant metastatic tumors has advanced with immunotherapies anti–PD-1, anti-PD-L1, and/or anti-CTLA4 proving efficacious, many patients remain unresponsive and chemotherapy with dacarbazine, temozolomide, or carboplatin show limited success.  There is a compelling rationale to examine unexploited pathways. Resistance has been attributed to subpopulations of “melanoma initiating cells”, highly tumorigenic cancer stem cells characterized by melanosphere formation, and expression of specific cancer stem cell markers. 

This Special Issue will publish original articles and reviews focusing on novel targets for therapeutic intervention, biomarkers for screening, predicting treatment response, and monitoring disease progression, and mechanistic insights and advances in molecular and cellular pathways involved in melanomagenesis and progression. Topics of interest include, mechanisms underlying melanoma progression and treatment response, signal transduction, melanoma initiating cells, drug resistance, invasiveness, immune evasion, and metastasis. There remains an urgent need to identify novel targets and develop new combinatorial therapeutic approaches that can overcome drug resistance mechanisms.

We  look forward to receiving your contributions to this Special Issue.

Dr. Dean S. Rosenthal
Dr. Cynthia Simbulan-Rosenthal
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • melanomagenesis
  • treatment response
  • signal transduction
  • melanoma initiating cells
  • drug resistance
  • invasiveness
  • immune evasion
  • metastasis
  • MAPK pathway
  • PI3K/AKT survival pathways
  • MEKi
  • BRAFi
  • trametinib
  • dabrafenib
  • immunotherapies

Published Papers (6 papers)

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Research

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19 pages, 1500 KiB  
Article
Daphnetin, a Coumarin with Anticancer Potential against Human Melanoma: In Vitro Study of Its Effective Combination with Selected Cytostatic Drugs
by Paula Wróblewska-Łuczka, Agnieszka Góralczyk and Jarogniew J. Łuszczki
Cells 2023, 12(12), 1593; https://doi.org/10.3390/cells12121593 - 09 Jun 2023
Cited by 1 | Viewed by 1308
Abstract
(1) The treatment of metastatic or drug-resistant melanoma is still a significant therapeutic problem. The aim of this study was to evaluate the anticancer potential of daphnetin (7,8-dihydroxycoumarin) and its combinations with five different cytostatic drugs (mitoxantrone, docetaxel, vemurafenib, epirubicin and cisplatin). (2) [...] Read more.
(1) The treatment of metastatic or drug-resistant melanoma is still a significant therapeutic problem. The aim of this study was to evaluate the anticancer potential of daphnetin (7,8-dihydroxycoumarin) and its combinations with five different cytostatic drugs (mitoxantrone, docetaxel, vemurafenib, epirubicin and cisplatin). (2) The viability, proliferation and cytotoxicity of daphnetin against four human malignant melanoma cell lines were evaluated. The interactions were assessed using isobolographic analysis for the combinations of daphnetin with each of the five cytostatic drugs. (3) Daphnetin showed anticancer activity against malignant melanoma, with IC50 values ranging from 40.48 ± 10.90 µM to 183.97 ± 18.82 µM, depending on the cell line. The combination of daphnetin with either vemurafenib or epirubicin showed an antagonistic interaction. Moreover, additive interactions were observed for the combinations of daphnetin with cisplatin and docetaxel. The most desirable synergistic interactions for human melanoma metastatic cell lines were observed for the combination of daphnetin with mitoxantrone. (4) The obtained results suggest that daphnetin should not be combined with vemurafenib or epirubicin in the treatment of malignant melanoma due to the abolition of their anticancer effects. The combination of daphnetin with mitoxantrone is beneficial in the treatment of metastatic melanoma due to their synergistic interaction. Full article
(This article belongs to the Special Issue Melanoma: From Molecular Mechanisms to Therapeutic Opportunities)
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18 pages, 5742 KiB  
Article
The Assessment of Anti-Melanoma Potential of Tigecycline—Cellular and Molecular Studies of Cell Proliferation, Apoptosis and Autophagy on Amelanotic and Melanotic Melanoma Cells
by Jakub Rok, Justyna Kowalska, Zuzanna Rzepka, Dominika Stencel, Anna Skorek, Klaudia Banach and Dorota Wrześniok
Cells 2023, 12(12), 1564; https://doi.org/10.3390/cells12121564 - 06 Jun 2023
Cited by 1 | Viewed by 1108
Abstract
High mortality, aggressiveness, and the relatively low effectiveness of therapy make melanoma the most dangerous of skin cancers. Previously published studies presented the promising therapeutic potential of minocycline, doxycycline, and chlortetracycline on melanoma cells. This study aimed to assess the cytotoxicity of tigecycline, [...] Read more.
High mortality, aggressiveness, and the relatively low effectiveness of therapy make melanoma the most dangerous of skin cancers. Previously published studies presented the promising therapeutic potential of minocycline, doxycycline, and chlortetracycline on melanoma cells. This study aimed to assess the cytotoxicity of tigecycline, a third-generation tetracycline, on melanotic (COLO 829) and amelanotic (A375) melanoma cell lines. The obtained results showed that tigecycline, proportionally to the concentration and incubation time, efficiently inhibited proliferation of both types of melanoma cells. The effect was accompanied by the dysregulation of the cell cycle, the depolarization of the mitochondrial membrane, and a decrease in the reduced thiols and the levels of MITF and p44/42 MAPK. However, the ability to induce apoptosis was only found in COLO 829 melanoma cells. A375 cells appeared to be more resistant to the treatment with tigecycline. The drug did not induce apoptosis but caused an increase in LC3A/B protein levels—an autophagy marker. The observed differences in drug action on the tested cell lines also involved an increase in p21 and p16 protein levels in melanotic melanoma, which was related to cell cycle arrest in the G1/G0 phase. The greater sensitivity of melanotic melanoma cells to the action of tigecycline suggests the possibility of considering the use of the drug in targeted therapy. Full article
(This article belongs to the Special Issue Melanoma: From Molecular Mechanisms to Therapeutic Opportunities)
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15 pages, 4255 KiB  
Article
The αMSH-Dependent PI3K Pathway Supports Energy Metabolism, via Glucose Uptake, in Melanoma Cells
by Giorgia Cardinali, Daniela Kovacs, Sarah Mosca, Barbara Bellei, Enrica Flori, Aldo Morrone, Anna Maria Mileo and Vittoria Maresca
Cells 2023, 12(7), 1099; https://doi.org/10.3390/cells12071099 - 06 Apr 2023
Cited by 1 | Viewed by 1534
Abstract
Stimulation of melanocytes and murine melanoma cells with αMSH plus the PI3K inhibitor LY294002 resulted in ROS increase, oxidative DNA damage, and pigment retention. We performed cellular and molecular biology assays (Western blot, FACS, immunofluorescence analysis, scratch assay) on murine and human melanoma [...] Read more.
Stimulation of melanocytes and murine melanoma cells with αMSH plus the PI3K inhibitor LY294002 resulted in ROS increase, oxidative DNA damage, and pigment retention. We performed cellular and molecular biology assays (Western blot, FACS, immunofluorescence analysis, scratch assay) on murine and human melanoma cells. Treatment with αMSH plus LY294002 altered cortical actin architecture. Given that cytoskeleton integrity requires energy, we next evaluated ATP levels and we observed a drop in ATP after exposure to αMSH plus LY294002. To evaluate if the αMSH-activated PI3K pathway could modulate energy metabolism, we focused on glucose uptake by analyzing the expression of the Glut-1 glucose translocator. Compared with cells treated with αMSH alone, those exposed to combined treatment showed a reduction of Glut-1 on the plasma membrane. This metabolic alteration was associated with changes in mitochondrial mass. A significant decrease of the cell migratory potential was also observed. We demonstrated that the αMSH-dependent PI3K pathway acts as a regulator of energy metabolism via glucose uptake, influencing the actin cytoskeleton, which is involved in melanosome release and cell motility. Hence, these results could constitute the basis for innovative therapeutical strategies. Full article
(This article belongs to the Special Issue Melanoma: From Molecular Mechanisms to Therapeutic Opportunities)
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16 pages, 2512 KiB  
Article
3D Spheroid Configurations Are Possible Indictors for Evaluating the Pathophysiology of Melanoma Cell Lines
by Hiroshi Ohguro, Megumi Watanabe, Tatsuya Sato, Fumihito Hikage, Masato Furuhashi, Masae Okura, Tokimasa Hida and Hisashi Uhara
Cells 2023, 12(5), 759; https://doi.org/10.3390/cells12050759 - 27 Feb 2023
Cited by 9 | Viewed by 2131
Abstract
To study the molecular mechanisms responsible for inducing the spatial proliferation of malignant melanomas (MM), three-dimension (3D) spheroids were produced from several MM cell lines including SK-mel-24, MM418, A375, WM266-4, and SM2-1, and their 3D architectures and cellular metabolisms were evaluated by phase-contrast [...] Read more.
To study the molecular mechanisms responsible for inducing the spatial proliferation of malignant melanomas (MM), three-dimension (3D) spheroids were produced from several MM cell lines including SK-mel-24, MM418, A375, WM266-4, and SM2-1, and their 3D architectures and cellular metabolisms were evaluated by phase-contrast microscopy and Seahorse bio-analyzer, respectively. Several transformed horizontal configurations were observed within most of these 3D spheroids, and the degree of their deformity was increased in the order: WM266-4, SM2-1, A375, MM418, and SK-mel-24. An increased maximal respiration and a decreased glycolytic capacity were observed within the lesser deformed two MM cell lines, WM266-4 and SM2-1, as compared with the most deformed ones. Among these MM cell lines, two distinct cell lines, WM266-4 and SK-mel-24, whose 3D appearances were the closest and farthest, respectively, from being horizontally circular-shaped, were subjected to RNA sequence analyses. Bioinformatic analyses of the differentially expressed genes (DEGs) identified KRAS and SOX2 as potential master regulatory genes for inducing these diverse 3D configurations between WM266-4 and SK-mel-24. The knockdown of both factors altered the morphological and functional characteristics of the SK-mel-24 cells, and in fact, their horizontal deformity was significantly reduced. A qPCR analysis indicated that the levels of several oncogenic signaling related factors, including KRAS and SOX2, PCG1α, extracellular matrixes (ECMs), and ZO1 had fluctuated among the five MM cell lines. In addition, and quite interestingly, the dabrafenib and trametinib resistant A375 (A375DT) cells formed globe shaped 3D spheroids and showed different profiles in cellular metabolism while the mRNA expression of these molecules that were tested as above were different compared with A375 cells. These current findings suggest that 3D spheroid configuration has the potential for serving as an indicator of the pathophysiological activities associated with MM. Full article
(This article belongs to the Special Issue Melanoma: From Molecular Mechanisms to Therapeutic Opportunities)
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Review

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25 pages, 4065 KiB  
Review
Adult and Pediatric Nail Unit Melanoma: Epidemiology, Diagnosis, and Treatment
by Jade Conway, Jane S. Bellet, Adam I. Rubin and Shari R. Lipner
Cells 2023, 12(6), 964; https://doi.org/10.3390/cells12060964 - 22 Mar 2023
Cited by 3 | Viewed by 15260
Abstract
Nail unit melanoma (NUM) is an uncommon form of melanoma and is often diagnosed at later stages. Approximately two-thirds of NUMs are present clinically as longitudinal melanonychia, but longitudinal melanonychia has a broad differential diagnosis. Clinical examination and dermoscopy are valuable for identifying [...] Read more.
Nail unit melanoma (NUM) is an uncommon form of melanoma and is often diagnosed at later stages. Approximately two-thirds of NUMs are present clinically as longitudinal melanonychia, but longitudinal melanonychia has a broad differential diagnosis. Clinical examination and dermoscopy are valuable for identifying nail findings concerning malignancy, but a biopsy with histopathology is necessary to confirm a diagnosis of NUM. Surgical treatment options for NUM include en bloc excision, digit amputation, and Mohs micrographic surgery. Newer treatments for advanced NUM include targeted and immune systemic therapies. NUM in pediatric patients is extremely rare and diagnosis is challenging since both qualitative and quantitative parameters have only been studied in adults. There is currently no consensus on management in children; for less concerning melanonychia, some physicians recommend close follow-up. However, some dermatologists argue that the “wait and see” approach can cause delayed diagnosis. This article serves to enhance the familiarity of NUM by highlighting its etiology, clinical presentations, diagnosis, and treatment options in both adults and children. Full article
(This article belongs to the Special Issue Melanoma: From Molecular Mechanisms to Therapeutic Opportunities)
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12 pages, 632 KiB  
Review
The Lysosome in Malignant Melanoma: Biology, Function and Therapeutic Applications
by Chia-Hsin Hsu, Keng-Jung Lee, Yi-Han Chiu, Kuo-Ching Huang, Guo-Shou Wang, Lei-Po Chen, Kuang-Wen Liao and Chen-Si Lin
Cells 2022, 11(9), 1492; https://doi.org/10.3390/cells11091492 - 29 Apr 2022
Cited by 7 | Viewed by 2359
Abstract
Lysosomes are membrane-bound vesicles that play roles in the degradation and recycling of cellular waste and homeostasis maintenance within cells. False alterations of lysosomal functions can lead to broad detrimental effects and cause various diseases, including cancers. Cancer cells that are rapidly proliferative [...] Read more.
Lysosomes are membrane-bound vesicles that play roles in the degradation and recycling of cellular waste and homeostasis maintenance within cells. False alterations of lysosomal functions can lead to broad detrimental effects and cause various diseases, including cancers. Cancer cells that are rapidly proliferative and invasive are highly dependent on effective lysosomal function. Malignant melanoma is the most lethal form of skin cancer, with high metastasis characteristics, drug resistance, and aggressiveness. It is critical to understand the role of lysosomes in melanoma pathogenesis in order to improve the outcomes of melanoma patients. In this mini-review, we compile our current knowledge of lysosomes’ role in tumorigenesis, progression, therapy resistance, and the current treatment strategies related to lysosomes in melanoma. Full article
(This article belongs to the Special Issue Melanoma: From Molecular Mechanisms to Therapeutic Opportunities)
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