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

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 41278

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Prof. Dr. Jochen Sven Utikal

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Guest Editor

Skin Cancer Unit, German Cancer Research Center (DKFZ) and University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany
Interests: malignant melanoma; melanoma cellular plasticity; therapy resistance; biomarkers; translational oncology
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Dear Colleagues,

Malignant melanoma is the deadliest skin cancer, associated with rising incidence rates. During recent years, new targeted therapies and immunotherapies have improved the outcome of patients with advanced malignant melanoma. However, phenotypic and metabolic heterogeneity of melanoma cells caused by cellular plasticity is a major barrier to effective cancer therapy. Deciphering the molecular basis of melanoma cellular plasticity has the potential to contribute to novel therapeutic strategies, which could lead to deeper and longer-lasting clinical responses.
In this Special Issue, we will publish reviews and original research that provide new insights into the molecular mechanisms of melanoma cellular plasticity.

Prof. Dr. Jochen Utikal
Guest Editor

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Keywords

Melanoma
Cellular plasticity
Resistance
Molecule
Targeted therapy
Immunotherapy
Pathogenesis
Treatment
Genetics
Epigenetics
Signaling pathways
Molecular mechanisms

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

3 pages, 167 KiB

Open AccessEditorial

Melanoma Cellular Plasticity

by Daniel Novak and Jochen Utikal

Int. J. Mol. Sci. 2022, 23(12), 6401; https://doi.org/10.3390/ijms23126401 - 8 Jun 2022

Viewed by 1384

Abstract

Despite the advances of modern medicine and the development of innovative and promising new therapeutic strategies for the treatment of the numerous types of cancer, far too many patients still lose the battle against these devastating diseases [...] Full article

(This article belongs to the Special Issue Melanoma Cellular Plasticity)

Research

Jump to: Editorial, Review

20 pages, 6085 KiB

Open AccessArticle

A Transcriptome-Wide Isoform Landscape of Melanocytic Nevi and Primary Melanomas Identifies Gene Isoforms Associated with Malignancy

by Siras Hakobyan, Henry Loeffler-Wirth, Arsen Arakelyan, Hans Binder and Manfred Kunz

Int. J. Mol. Sci. 2021, 22(13), 7165; https://doi.org/10.3390/ijms22137165 - 2 Jul 2021

Cited by 8 | Viewed by 3390

Abstract

Genetic splice variants have become of central interest in recent years, as they play an important role in different cancers. Little is known about splice variants in melanoma. Here, we analyzed a genome-wide transcriptomic dataset of benign melanocytic nevi and primary melanomas (n = 80) for the expression of specific splice variants. Using kallisto, a map for differentially expressed splice variants in melanoma vs. benign melanocytic nevi was generated. Among the top genes with differentially expressed splice variants were Ras-related in brain 6B (RAB6B), a member of the RAS family of GTPases, Macrophage Scavenger Receptor 1 (MSR1), Collagen Type XI Alpha 2 Chain (COLL11A2), and LY6/PLAUR Domain Containing 1 (LYPD1). The Gene Ontology terms of differentially expressed splice variants showed no enrichment for functional gene sets of melanoma vs. nevus lesions, but between type 1 (pigmentation type) and type 2 (immune response type) melanocytic lesions. A number of genes such as Checkpoint Kinase 1 (CHEK1) showed an association of mutational patterns and occurrence of splice variants in melanoma. Moreover, mutations in genes of the splicing machinery were common in both benign nevi and melanomas, suggesting a common mechanism starting early in melanoma development. Mutations in some of these genes of the splicing machinery, such as Serine and Arginine Rich Splicing Factor A3 and B3 (SF3A3, SF3B3), were significantly enriched in melanomas as compared to benign nevi. Taken together, a map of splice variants in melanoma is presented that shows a multitude of differentially expressed splice genes between benign nevi and primary melanomas. The underlying mechanisms may involve mutations in genes of the splicing machinery. Full article

(This article belongs to the Special Issue Melanoma Cellular Plasticity)

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21 pages, 8665 KiB

Open AccessArticle

In Vitro Effects of Selective COX and LOX Inhibitors and Their Combinations with Antineoplastic Drugs in the Mouse Melanoma Cell Line B16F10

by Ines Da-Costa-Rocha and Jose M. Prieto

Int. J. Mol. Sci. 2021, 22(12), 6498; https://doi.org/10.3390/ijms22126498 - 17 Jun 2021

Cited by 10 | Viewed by 3203

Abstract

The constitutive expression or overactivation of cyclooxygenase (COX) and lipoxygenase (LOX) enzymes results in aberrant metabolism of arachidonic acid and poor prognosis in melanoma. Our aim is to compare the in vitro effects of selective COX-1 (acetylsalicylic acid), COX-2 (meloxicam), 5-LOX (MK-886 and AA-861), 12-LOX (baicalein) and 15-LOX (PD-146176) inhibition in terms of proliferation (SRB assay), mitochondrial viability (MTT assay), caspase 3-7 activity (chemiluminescent assay), 2D antimigratory (scratch assay) and synthesis of eicosanoids (EIA) in the B16F10 cell line (single treatments). We also explore their combinatorial pharmacological space with dacarbazine and temozolomide (median effect method). Overall, our results with single treatments show a superior cytotoxic efficacy of selective LOX inhibitors over selective COX inhibitors against B16F10 cells. PD-146176 caused the strongest antiproliferation effect which was accompanied by cell cycle arrest in G₁ phase and an >50-fold increase in caspases 3/7 activity. When the selected inhibitors are combined with the antineoplastic drugs, only meloxicam provides clear synergy, with LOX inhibitors mostly antagonizing. These apparent contradictions between single and combination treatments, together with some paradoxical effects observed in the biosynthesis of eicosanoids after FLAP inhibition in short term incubations, warrant further mechanistical in vitro and in vivo scrutiny. Full article

(This article belongs to the Special Issue Melanoma Cellular Plasticity)

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16 pages, 3107 KiB

Open AccessArticle

UVA Radiation Enhances Lomefloxacin-Mediated Cytotoxic, Growth-Inhibitory and Pro-Apoptotic Effect in Human Melanoma Cells through Excessive Reactive Oxygen Species Generation

by Artur Beberok, Zuzanna Rzepka, Jakub Rok, Klaudia Banach and Dorota Wrześniok

Int. J. Mol. Sci. 2020, 21(23), 8937; https://doi.org/10.3390/ijms21238937 - 25 Nov 2020

Cited by 5 | Viewed by 2126

Abstract

Melanoma, the most dangerous type of cutaneous neoplasia, contributes to about 75% of all skin cancer-related deaths. Thus, searching for new melanoma treatment options is an important field of study. The current study was designed to assess whether the condition of mild and low-dose UVA radiation augments the lomefloxacin-mediated cytotoxic, growth-inhibitory and pro-apoptotic effect of the drug in melanoma cancer cells through excessive oxidative stress generation. C32 amelanotic and COLO829 melanotic (BRAF-mutant) melanoma cell lines were used as an experimental model system. The combined exposure of cells to both lomefloxacin and UVA irradiation caused higher alterations of redox signalling pathways, as shown by intracellular reactive oxygen species overproduction and endogenous glutathione depletion when compared to non-irradiated but lomefloxacin-treated melanoma cells. The obtained results also showed that lomefloxacin decreased both C32 and COLO829 cells’ viability in a concentration-dependent manner. This effect significantly intensified when melanoma cells were exposed to UVA irradiation and the drug. For melanoma cells exposed to lomefloxacin or lomefloxacin co-treatment with UVA irradiation, the concentrations of the drug that decreased the cells’ viability by 50% (EC₅₀) were found to be 0.97, 0.17, 1.01, 0.18 mM, respectively. Moreover, we found that the redox imbalance, mitochondrial membrane potential breakdown, induction of DNA fragmentation, and changes in the melanoma cells’ cell cycle distribution (including G₂/M, S as well as Sub-G₁-phase blockade) were lomefloxacin in a dose-dependent manner and were significantly augmented by UVA radiation. This is the first experimental work that assesses the impact of excessive reactive oxygen species generation upon UVA radiation exposure on lomefloxacin-mediated cytotoxic, growth-inhibitory and pro-apoptotic effects towards human melanoma cells, indicating the possibility of the usage of this drug in the photochemotherapy of malignant melanoma as an innovative medical treatment option which could improve the effectiveness of therapy. The obtained results also revealed that the redox imbalance intensification mediated by the phototoxic potential of fluoroquinolones may be considered as a more efficient treatment model of malignant melanoma and may constitute the basis for the development of new compounds with a high ability to excessive oxidative stress generation upon UVA radiation in cancer cells. Full article

(This article belongs to the Special Issue Melanoma Cellular Plasticity)

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22 pages, 5180 KiB

Open AccessArticle

Analysis of Melanoma Secretome for Factors That Directly Disrupt the Barrier Integrity of Brain Endothelial Cells

by Akshata Anchan, Olivia Martin, James J. W. Hucklesby, Graeme Finlay, Rebecca H. Johnson, Laverne D. Robilliard, Simon J. O’Carroll, Catherine E. Angel and E Scott Graham

Int. J. Mol. Sci. 2020, 21(21), 8193; https://doi.org/10.3390/ijms21218193 - 1 Nov 2020

Cited by 9 | Viewed by 3201

Abstract

We have recently demonstrated that invasive melanoma cells are capable of disrupting the brain endothelial barrier integrity. This was shown using ECIS biosensor technology, which revealed rapid disruption via the paracellular junctions. In this paper, we demonstrate that melanoma cells secrete factors (e.g., cytokines) that weaken the endothelial barrier integrity. Through proteome profiling, we attempt to identify the barrier-disrupting cytokines. Melanoma conditioned media were collected from three New Zealand melanoma lines. ECIS technology was used to assess if the conditioned media disrupted the endothelial barrier independent of the melanoma cells. The melanoma cell secretome was assessed using cytometric bead array (CBA), Luminex immunoassay and multiplex Proteome Profilers, to detect the expression of secretory proteins, which may facilitate metastasis. Finally, ECIS technology was used to assess the direct effects of secreted proteins identified as candidates from the proteome screens. We show that melanoma-conditioned media significantly disrupted the brain endothelial barrier, however, to a much lesser extent than the cells from which they were collected. Cytokine and proteome profiling of the conditioned media showed evidence of high concentrations of approximately 15 secreted proteins (including osteopontin, IL-8, GDF-15, MIF and VEGF). These 15 secreted proteins were expressed variably across the melanoma lines. Surprisingly, the addition of these individually to the brain endothelial cells did not substantially affect the barrier integrity. ANGPTL-4 and TGFβ were also produced by the melanoma cells. Whilst TGFβ-1 had a pronounced effect on the barrier integrity, surprisingly ANGPTL-4 did not. However, its C-terminal fragment did and within a very similar period to the conditioned media, albeit not to the same extent. Herein we show that melanoma cells produce a wide-range of soluble factors at high concentrations, which most likely favour support or survival of the cancer cells. Most of these, except for TGFβ-1 and the C-terminal fragment of ANGPTL-4, did not have an impact on the integrity of the brain endothelial cells. Full article

(This article belongs to the Special Issue Melanoma Cellular Plasticity)

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Review

Jump to: Editorial, Research

18 pages, 1412 KiB

Open AccessReview

How Neural Crest Transcription Factors Contribute to Melanoma Heterogeneity, Cellular Plasticity, and Treatment Resistance

by Anja Wessely, Theresa Steeb, Carola Berking and Markus Vincent Heppt

Int. J. Mol. Sci. 2021, 22(11), 5761; https://doi.org/10.3390/ijms22115761 - 28 May 2021

Cited by 21 | Viewed by 6517

Abstract

Cutaneous melanoma represents one of the deadliest types of skin cancer. The prognosis strongly depends on the disease stage, thus early detection is crucial. New therapies, including BRAF and MEK inhibitors and immunotherapies, have significantly improved the survival of patients in the last decade. However, intrinsic and acquired resistance is still a challenge. In this review, we discuss two major aspects that contribute to the aggressiveness of melanoma, namely, the embryonic origin of melanocytes and melanoma cells and cellular plasticity. First, we summarize the physiological function of epidermal melanocytes and their development from precursor cells that originate from the neural crest (NC). Next, we discuss the concepts of intratumoral heterogeneity, cellular plasticity, and phenotype switching that enable melanoma to adapt to changes in the tumor microenvironment and promote disease progression and drug resistance. Finally, we further dissect the connection of these two aspects by focusing on the transcriptional regulators MSX1, MITF, SOX10, PAX3, and FOXD3. These factors play a key role in NC initiation, NC cell migration, and melanocyte formation, and we discuss how they contribute to cellular plasticity and drug resistance in melanoma. Full article

(This article belongs to the Special Issue Melanoma Cellular Plasticity)

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24 pages, 1955 KiB

Open AccessReview

Influence of Tumor Microenvironment and Fibroblast Population Plasticity on Melanoma Growth, Therapy Resistance and Immunoescape

by Veronica Romano, Immacolata Belviso, Alessandro Venuta, Maria Rosaria Ruocco, Stefania Masone, Federica Aliotta, Giuseppe Fiume, Stefania Montagnani, Angelica Avagliano and Alessandro Arcucci

Int. J. Mol. Sci. 2021, 22(10), 5283; https://doi.org/10.3390/ijms22105283 - 17 May 2021

Cited by 34 | Viewed by 4370

Abstract

Cutaneous melanoma (CM) tissue represents a network constituted by cancer cells and tumor microenvironment (TME). A key feature of CM is the high structural and cellular plasticity of TME, allowing its evolution with disease and adaptation to cancer cell and environmental alterations. In particular, during melanoma development and progression each component of TME by interacting with each other and with cancer cells is subjected to dramatic structural and cellular modifications. These alterations affect extracellular matrix (ECM) remodelling, phenotypic profile of stromal cells, cancer growth and therapeutic response. The stromal fibroblast populations of the TME include normal fibroblasts and melanoma-associated fibroblasts (MAFs) that are highly abundant and flexible cell types interacting with melanoma and stromal cells and differently influencing CM outcomes. The shift from the normal microenvironment to TME and from normal fibroblasts to MAFs deeply sustains CM growth. Hence, in this article we review the features of the normal microenvironment and TME and describe the phenotypic plasticity of normal dermal fibroblasts and MAFs, highlighting their roles in normal skin homeostasis and TME regulation. Moreover, we discuss the influence of MAFs and their secretory profiles on TME remodelling, melanoma progression, targeted therapy resistance and immunosurveillance, highlighting the cellular interactions, the signalling pathways and molecules involved in these processes. Full article

(This article belongs to the Special Issue Melanoma Cellular Plasticity)

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15 pages, 251 KiB

Open AccessReview

Clinical Implications of Acquired BRAF Inhibitors Resistance in Melanoma

by Paola Savoia, Elisa Zavattaro and Ottavio Cremona

Int. J. Mol. Sci. 2020, 21(24), 9730; https://doi.org/10.3390/ijms21249730 - 20 Dec 2020

Cited by 22 | Viewed by 2770

Abstract

Understanding the role of mitogen-activated protein kinase (MAPK) pathway-activating mutations in the development and progression of melanoma and their possible use as therapeutic targets has substantially changed the management of this neoplasm, which, until a few years ago, was burdened by severe mortality. However, the presence of numerous intrinsic and extrinsic mechanisms of resistance to BRAF inhibitors compromises the treatment responses’ effectiveness and durability. The strategy of overcoming these resistances by combination therapy has proved successful, with the additional benefit of reducing side effects derived from paradoxical activation of the MAPK pathway. Furthermore, the use of other highly specific inhibitors, intermittent dosing schedules and the association of combination therapy with immune checkpoint inhibitors are promising new therapeutic strategies. However, numerous issues related to dose, tolerability and administration sequence still need to be clarified, as is to be expected from currently ongoing trials. In this review, we describe the clinical results of using BRAF inhibitors in advanced melanoma, with a keen interest in strategies aimed at overcoming resistance. Full article

(This article belongs to the Special Issue Melanoma Cellular Plasticity)

28 pages, 959 KiB

Open AccessReview

The Influence of Tumor Microenvironment on Immune Escape of Melanoma

by Aleksandra Simiczyjew, Ewelina Dratkiewicz, Justyna Mazurkiewicz, Marcin Ziętek, Rafał Matkowski and Dorota Nowak

Int. J. Mol. Sci. 2020, 21(21), 8359; https://doi.org/10.3390/ijms21218359 - 7 Nov 2020

Cited by 86 | Viewed by 6842

Abstract

The low efficiency of currently-used anti-cancer therapies poses a serious challenge, especially in the case of malignant melanoma, a cancer characterized by elevated invasiveness and relatively high mortality rate. The role of the tumor microenvironment in the progression of melanoma and its acquisition of resistance to treatment seems to be the main focus of recent studies. One of the factors that, in normal conditions, aids the organism in its fight against the cancer and, following the malignant transformation, adapts to facilitate the development of the tumor is the immune system. A variety of cell types, i.e., T and B lymphocytes, macrophages, and dendritic and natural killer cells, as well as neutrophils, support the growth and invasiveness of melanoma cells, utilizing a plethora of mechanisms, including secretion of pro-inflammatory molecules, induction of inhibitory receptors expression, or depletion of essential nutrients. This review provides a comprehensive summary of the processes regulated by tumor-associated cells that promote the immune escape of melanoma cells. The described mechanisms offer potential new targets for anti-cancer treatment and should be further studied to improve currently-employed therapies. Full article

(This article belongs to the Special Issue Melanoma Cellular Plasticity)

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14 pages, 1869 KiB

Open AccessReview

Cellular Reprogramming—A Model for Melanoma Cellular Plasticity

by Karol Granados, Juliane Poelchen, Daniel Novak and Jochen Utikal

Int. J. Mol. Sci. 2020, 21(21), 8274; https://doi.org/10.3390/ijms21218274 - 5 Nov 2020

Cited by 15 | Viewed by 6439

Abstract

Cellular plasticity of cancer cells is often associated with phenotypic heterogeneity and drug resistance and thus remains a major challenge for the treatment of melanoma and other types of cancer. Melanoma cells have the capacity to switch their phenotype during tumor progression, from a proliferative and differentiated phenotype to a more invasive and dedifferentiated phenotype. However, the molecular mechanisms driving this phenotype switch are not yet fully understood. Considering that cellular heterogeneity within the tumor contributes to the high plasticity typically observed in melanoma, it is crucial to generate suitable models to investigate this phenomenon in detail. Here, we discuss the use of complete and partial reprogramming into induced pluripotent cancer (iPC) cells as a tool to obtain new insights into melanoma cellular plasticity. We consider this a relevant topic due to the high plasticity of melanoma cells and its association with a strong resistance to standard anticancer treatments. Full article

(This article belongs to the Special Issue Melanoma Cellular Plasticity)

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