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Cells
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Recent Advances in the Field of Metastatic Melanoma
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Recent Advances in the Field of Metastatic Melanoma

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

Deadline for manuscript submissions: closed (25 June 2024) | Viewed by 12213

Special Issue Editor

Dr. Yanlin Yu

E-Mail Website
Guest Editor
Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute (NCI-CCR), Bethesda, MD 20852, USA
Interests: tumor metastasis; mouse models; tumor immunology; drug resistance; Ezrin; PTEN

Special Issue Information

Dear Colleagues,

Cutaneous melanoma represents one of the most aggressive and difficult-to-treat forms of human cancer, with a worldwide incidence that has steadily increased over the past half a century. Although the majority of melanomas are successfully treated with surgical excision, most patients with metastatic melanoma do not benefit from surgery due to metastasis. Despite more therapeutic advances, metastatic melanoma still has poor long-term outcomes. Targeted therapies, such as BRAF and MEK inhibitors, have dramatically improved the prognosis of patients with metastatic melanoma bearing specific gene alterations. However, acquired resistance rapidly develops, hindering the durable efficacy of these therapies. In recent years, immunotherapy has demonstrated a durable response in half of the patients with metastatic melanoma. At the same time, half of these patients experience side effects with severe autoimmune adverse events. Therefore, uncovering the characteristics of metastatic melanoma and new therapeutic strategies is critical for fighting the deadliest metastatic melanoma diseases. In this Issue, we will discuss the frontiers in the field of metastatic melanoma research concerning biological and genetic mechanisms, targeted therapy, immunotherapy, and combination therapy in clinical and basial research.

Dr. Yanlin Yu
Guest Editor

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Keywords

  • molecular mechanism
  • microenvironment
  • immune escape
  • metabolism reprograming
  • targeted therapy
  • immunotherapy
  • organoid and 3D culture
  • drug development

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Published Papers (6 papers)

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Research

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15 pages, 7728 KiB  
Article
Deregulation of Metalloproteinase Expression in Gray Horse Melanoma Ex Vivo and In Vitro
by Daniela M. Brodesser, Stefan Kummer, Julia A. Eichberger, Karin Schlangen, Annunziata Corteggio, Giuseppe Borzacchiello, Christof A. Bertram, Sabine Brandt and Barbara Pratscher
Cells 2024, 13(11), 956; https://doi.org/10.3390/cells13110956 - 31 May 2024
Viewed by 813
Abstract
The ability of human melanoma cells to switch from an epithelial to a mesenchymal phenotype contributes to the metastatic potential of disease. Metalloproteinases (MPs) are crucially involved in this process by promoting the detachment of tumor cells from the primary lesion and their [...] Read more.
The ability of human melanoma cells to switch from an epithelial to a mesenchymal phenotype contributes to the metastatic potential of disease. Metalloproteinases (MPs) are crucially involved in this process by promoting the detachment of tumor cells from the primary lesion and their migration to the vasculature. In gray horse melanoma, epithelial–mesenchymal transition (EMT) is poorly understood, prompting us to address MP expression in lesions versus intact skin by transcriptome analyses and the immunofluorescence staining (IF) of gray horse tumor tissue and primary melanoma cells. RNAseq revealed the deregulation of several MPs in gray horse melanoma and, notably, a 125-fold upregulation of matrix metalloproteinase 1 (MMP1) that was further confirmed by RT-qPCR from additional tumor material. The IF staining of melanoma tissue versus intact skin for MMP1 and tumor marker S100 revealed MMP1 expression in all lesions. The co-expression of S100 was observed at different extents, with some tumors scoring S100-negative. The IF staining of primary tumor cells explanted from the tumors for MMP1 showed that the metalloproteinase is uniformly expressed in the cytoplasm of 100% of tumor cells. Overall, the presented data point to MP expression being deregulated in gray horse melanoma, and suggest that MMP1 has an active role in gray horse melanoma by driving EMT-mediated tumor cell dissemination via the degradation of the extracellular matrix. Whilst S100 is considered a reliable tumor marker in human MM, gray horse melanomas do not seem to regularly express this protein. Full article
(This article belongs to the Special Issue Recent Advances in the Field of Metastatic Melanoma)
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16 pages, 3364 KiB  
Article
Exploring the Interplay of RUNX2 and CXCR4 in Melanoma Progression
by Luca Dalle Carbonare, Arianna Minoia, Anna Vareschi, Francesca Cristiana Piritore, Sharazed Zouari, Alberto Gandini, Mirko Meneghel, Rossella Elia, Pamela Lorenzi, Franco Antoniazzi, João Pessoa, Donato Zipeto, Maria Grazia Romanelli, Daniele Guardavaccaro and Maria Teresa Valenti
Cells 2024, 13(5), 408; https://doi.org/10.3390/cells13050408 - 27 Feb 2024
Cited by 2 | Viewed by 1444
Abstract
Overexpression of the Runt-related transcription factor 2 (RUNX2) has been reported in several cancer types, and the C-X-C motif chemokine receptor 4 (CXCR4) has an important role in tumour progression. However, the interplay between CXCR4 and RUNX2 in melanoma [...] Read more.
Overexpression of the Runt-related transcription factor 2 (RUNX2) has been reported in several cancer types, and the C-X-C motif chemokine receptor 4 (CXCR4) has an important role in tumour progression. However, the interplay between CXCR4 and RUNX2 in melanoma cells remains poorly understood. In the present study, we used melanoma cells and a RUNX2 knockout (RUNX2-KO) in vitro model to assess the influence of RUNX2 on CXCR4 protein levels along with its effects on markers associated with cell invasion and autophagy. Osteotropism was assessed using a 3D microfluidic model. Moreover, we assessed the impact of CXCR4 on the cellular levels of key cellular signalling proteins involved in autophagy. We observed that melanoma cells express both RUNX2 and CXCR4. Restored RUNX2 expression in RUNX2 KO cells increased the expression levels of CXCR4 and proteins associated with the metastatic process. The protein markers of autophagy LC3 and beclin were upregulated in response to increased CXCR4 levels. The CXCR4 inhibitor WZ811 reduced osteotropism and activated the mTOR and p70-S6 cell signalling proteins. Our data indicate that the RUNX2 transcription factor promotes the expression of the CXCR4 chemokine receptor on melanoma cells, which in turn promotes autophagy, cell invasiveness, and osteotropism, through the inhibition of the mTOR signalling pathway. Our data suggest that RUNX2 promotes melanoma progression by upregulating CXCR4, and we identify the latter as a key player in melanoma-related osteotropism. Full article
(This article belongs to the Special Issue Recent Advances in the Field of Metastatic Melanoma)
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15 pages, 3662 KiB  
Article
The Development of Nonthermal Plasma and Tirapazamine as a Novel Combination Therapy to Treat Melanoma In Situ
by Matthew Yehl, Dominik Kucharski, Michelle Eubank, Brandon Gulledge, Gamal Rayan, Md Gias Uddin, Genevieve Remmers, Eugene S. Kandel, Douglas P. DuFaux, Timothy C. Hutcherson, Sandra Sexton and Shoshanna N. Zucker
Cells 2023, 12(16), 2113; https://doi.org/10.3390/cells12162113 - 21 Aug 2023
Cited by 1 | Viewed by 1830
Abstract
Although melanoma accounts for only 5.3% of skin cancer, it results in >75% of skin-cancer-related deaths. To avoid disfiguring surgeries on the head and neck associated with surgical excision, there is a clear unmet need for other strategies to selectively remove cutaneous melanoma [...] Read more.
Although melanoma accounts for only 5.3% of skin cancer, it results in >75% of skin-cancer-related deaths. To avoid disfiguring surgeries on the head and neck associated with surgical excision, there is a clear unmet need for other strategies to selectively remove cutaneous melanoma lesions. Mohs surgery is the current treatment for cutaneous melanoma lesions and squamous and basal cell carcinoma. While Mohs surgery is an effective way to remove melanomas in situ, normal tissue is also excised to achieve histologically negative margins. This paper describes a novel combination therapy of nonthermal plasma (NTP) which emits a multitude of reactive oxygen species (ROS) and the injection of a pharmaceutical agent. We have shown that the effects of NTP are augmented by the DNA-damaging prodrug, tirapazamine (TPZ), which becomes a free radical only in conditions of hypoxemia, which is often enhanced in the tumor microenvironment. In this study, we demonstrate the efficacy of the combination therapy through experiments with B16-F10 and 1205 Lu metastatic melanoma cells both in vitro and in vivo. We also show the safety parameters of the therapy with no significant effects of the therapy when applied to porcine skin. We show the need for the intratumor delivery of TPZ in combination with the surface treatment of NTP and present a model of a medical device to deliver this combination therapy. The importance of functional gap junctions is indicated as a mechanism to promote the therapeutic effect. Collectively, the data support a novel therapeutic combination to treat melanoma and the development of a medical device to deliver the treatment in situ. Full article
(This article belongs to the Special Issue Recent Advances in the Field of Metastatic Melanoma)
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Review

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29 pages, 1383 KiB  
Review
Promising and Minimally Invasive Biomarkers: Targeting Melanoma
by Pavlina Spiliopoulou, Carlos Diego Holanda Lopes and Anna Spreafico
Cells 2024, 13(1), 19; https://doi.org/10.3390/cells13010019 - 20 Dec 2023
Cited by 5 | Viewed by 2145
Abstract
The therapeutic landscape of malignant melanoma has been radically reformed in recent years, with novel treatments emerging in both the field of cancer immunotherapy and signalling pathway inhibition. Large-scale tumour genomic characterization has accurately classified malignant melanoma into four different genomic subtypes so [...] Read more.
The therapeutic landscape of malignant melanoma has been radically reformed in recent years, with novel treatments emerging in both the field of cancer immunotherapy and signalling pathway inhibition. Large-scale tumour genomic characterization has accurately classified malignant melanoma into four different genomic subtypes so far. Despite this, only somatic mutations in BRAF oncogene, as assessed in tumour biopsies, has so far become a validated predictive biomarker of treatment with small molecule inhibitors. The biology of tumour evolution and heterogeneity has uncovered the current limitations associated with decoding genomic drivers based only on a single-site tumour biopsy. There is an urgent need to develop minimally invasive biomarkers that accurately reflect the real-time evolution of melanoma and that allow for streamlined collection, analysis, and interpretation. These will enable us to face challenges with tumour tissue attainment and process and will fulfil the vision of utilizing “liquid biopsy” to guide clinical decisions, in a manner akin to how it is used in the management of haematological malignancies. In this review, we will summarize the most recent published evidence on the role of minimally invasive biomarkers in melanoma, commenting on their future potential to lead to practice-changing discoveries. Full article
(This article belongs to the Special Issue Recent Advances in the Field of Metastatic Melanoma)
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31 pages, 2104 KiB  
Review
CAR NK Cell Therapy for the Treatment of Metastatic Melanoma: Potential & Prospects
by Winston Hibler, Glenn Merlino and Yanlin Yu
Cells 2023, 12(23), 2750; https://doi.org/10.3390/cells12232750 - 30 Nov 2023
Cited by 1 | Viewed by 3175
Abstract
Melanoma is among the most lethal forms of cancer, accounting for 80% of deaths despite comprising just 5% of skin cancer cases. Treatment options remain limited due to the genetic and epigenetic mechanisms associated with melanoma heterogeneity that underlie the rapid development of [...] Read more.
Melanoma is among the most lethal forms of cancer, accounting for 80% of deaths despite comprising just 5% of skin cancer cases. Treatment options remain limited due to the genetic and epigenetic mechanisms associated with melanoma heterogeneity that underlie the rapid development of secondary drug resistance. For this reason, the development of novel treatments remains paramount to the improvement of patient outcomes. Although the advent of chimeric antigen receptor-expressing T (CAR-T) cell immunotherapies has led to many clinical successes for hematological malignancies, these treatments are limited in their utility by their immune-induced side effects and a high risk of systemic toxicities. CAR natural killer (CAR-NK) cell immunotherapies are a particularly promising alternative to CAR-T cell immunotherapies, as they offer a more favorable safety profile and have the capacity for fine-tuned cytotoxic activity. In this review, the discussion of the prospects and potential of CAR-NK cell immunotherapies touches upon the clinical contexts of melanoma, the immunobiology of NK cells, the immunosuppressive barriers preventing endogenous immune cells from eliminating tumors, and the structure and design of chimeric antigen receptors, then finishes with a series of proposed design innovations that could improve the efficacy CAR-NK cell immunotherapies in future studies. Full article
(This article belongs to the Special Issue Recent Advances in the Field of Metastatic Melanoma)
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18 pages, 1734 KiB  
Review
PAK1 and Therapy Resistance in Melanoma
by Julia V. Kichina, Alexei Maslov and Eugene S. Kandel
Cells 2023, 12(19), 2373; https://doi.org/10.3390/cells12192373 - 28 Sep 2023
Cited by 6 | Viewed by 1925
Abstract
Malignant melanoma claims more lives than any other skin malignancy. While primary melanomas are usually cured via surgical excision, the metastatic form of the disease portents a poor prognosis. Decades of intense research has yielded an extensive armamentarium of anti-melanoma therapies, ranging from [...] Read more.
Malignant melanoma claims more lives than any other skin malignancy. While primary melanomas are usually cured via surgical excision, the metastatic form of the disease portents a poor prognosis. Decades of intense research has yielded an extensive armamentarium of anti-melanoma therapies, ranging from genotoxic chemo- and radiotherapies to targeted interventions in specific signaling pathways and immune functions. Unfortunately, even the most up-to-date embodiments of these therapies are not curative for the majority of metastatic melanoma patients, and the need to improve their efficacy is widely recognized. Here, we review the reports that implicate p21-regulated kinase 1 (PAK1) and PAK1-related pathways in the response of melanoma to various therapeutic modalities. Ample data suggest that PAK1 may decrease cell sensitivity to programmed cell death, provide additional stimulation to growth-promoting molecular pathways, and contribute to the creation of an immunosuppressive tumor microenvironment. Accordingly, there is mounting evidence that the concomitant inhibition of PAK1 enhances the potency of various anti-melanoma regimens. Overall, the available information suggests that a safe and effective inhibition of PAK1-dependent molecular processes would enhance the potency of the currently available anti-melanoma treatments, although considerable challenges in implementing such strategies still exist. Full article
(This article belongs to the Special Issue Recent Advances in the Field of Metastatic Melanoma)
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