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Cancers
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Cellular Differentiation in Melanoma Development
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Cellular Differentiation in Melanoma Development

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 32140

Special Issue Editor

Prof. Dr. Mario Mikula

E-Mail Website
Guest Editor
Medical University of Vienna Institute of Medical Genetics Währinger Straße 10, 1090 Vienna, Austria
Interests: Melanoma metastasis; stem cells differentiation; phenotype switching controlled by signalling pathways

Special Issue Information

Dear Colleagues,

Melanocytic differentiation has been achieved starting from different cell sources like human neural crest stem cells or even human pluripotent stem cells. Therefore factors controlling differentiation of melanocytes are well defined. For neural crest induction BMP as well as TGF-beta inhibition and subsequent WNT activation is essential. Additionally melanocyte specification is increased when endothelin and BMP signalling is induced. This sequence of events leads to expression of SOX10 and MITF, which furthermore trigger formation of melanocyte-associated markers and melanin production.

While our knowledge on differentiation factors and associated pathways has increased over time, the impact of differentiation on melanoma onset and progression has not been studied in detail. Malignant melanoma is an aggressive disease hallmarked by the ability of cancer cells to undergo repeated phenotypic changes. These changes are reminiscent of developmental programs where cells either perform extensive proliferation or switch to an increasingly migratory and invasive behaviour without any signs of cell proliferation. This so called phenotype switching represents the major obstacle in melanoma therapy since it can induce tumour dormancy, resistance, metabolic changes, epigenetic reprogramming and other mechanisms contributing to recurrence of the disease.

Transplantation studies of melanoma cells in zebra fish and mice have indicated that embryonic environments can modulate the aggressiveness of cancer cells. Hence there is hope that external differentiation factors can trigger benign growth characteristics. This Special Issue will highlight current pathways modulating melanoma differentiation and explore its functional outcome as well as its therapeutic implications.

Prof. Dr. Mario Mikula
Guest Editor

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 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. Cancers 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 2900 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

  • malignant melanoma
  • mechanisms of differentiation
  • cKIT
  • SOX10
  • MITF
  • PAX3
  • cell cycle
  • endothelin pathway
  • melanin production
  • pigmentation
  • epithelial mesenchymal transition
  • EMT
  • metastasis

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Published Papers (6 papers)

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Research

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14 pages, 2376 KiB  
Article
Sustained Inflammatory Signalling through Stat1/Stat2/IRF9 Is Associated with Amoeboid Phenotype of Melanoma Cells
by Aneta Gandalovičová, Anna-Marie Šůchová, Vladimír Čermák, Ladislav Merta, Daniel Rösel and Jan Brábek
Cancers 2020, 12(9), 2450; https://doi.org/10.3390/cancers12092450 - 28 Aug 2020
Cited by 4 | Viewed by 3569
Abstract
The invasive behaviour of cancer cells underlies metastatic dissemination; however, due to the large plasticity of invasion modes, it is challenging to target. It is now widely accepted that various secreted cytokines modulate the tumour microenvironment and pro-inflammatory signalling can promote tumour progression. [...] Read more.
The invasive behaviour of cancer cells underlies metastatic dissemination; however, due to the large plasticity of invasion modes, it is challenging to target. It is now widely accepted that various secreted cytokines modulate the tumour microenvironment and pro-inflammatory signalling can promote tumour progression. Here, we report that cells after mesenchymal–amoeboid transition show the increased expression of genes associated with the type I interferon response. Moreover, the sustained activation of type I interferon signalling in response to IFNβ mediated by the Stat1/Stat2/IRF9 complex enhances the round amoeboid phenotype in melanoma cells, whereas its downregulation by various approaches promotes the mesenchymal invasive phenotype. Overall, we demonstrate that interferon signalling is associated with the amoeboid phenotype of cancer cells and suggest a novel role of IFNβ in promoting cancer invasion plasticity, aside from its known role as a tumour suppressor. Full article
(This article belongs to the Special Issue Cellular Differentiation in Melanoma Development)
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Review

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33 pages, 1334 KiB  
Review
Lipid metabolic Reprogramming: Role in Melanoma Progression and Therapeutic Perspectives
by Laurence Pellerin, Lorry Carrié, Carine Dufau, Laurence Nieto, Bruno Ségui, Thierry Levade, Joëlle Riond and Nathalie Andrieu-Abadie
Cancers 2020, 12(11), 3147; https://doi.org/10.3390/cancers12113147 - 27 Oct 2020
Cited by 37 | Viewed by 6286
Abstract
Metabolic reprogramming contributes to the pathogenesis and heterogeneity of melanoma. It is driven both by oncogenic events and the constraints imposed by a nutrient- and oxygen-scarce microenvironment. Among the most prominent metabolic reprogramming features is an increased rate of lipid synthesis. Lipids serve [...] Read more.
Metabolic reprogramming contributes to the pathogenesis and heterogeneity of melanoma. It is driven both by oncogenic events and the constraints imposed by a nutrient- and oxygen-scarce microenvironment. Among the most prominent metabolic reprogramming features is an increased rate of lipid synthesis. Lipids serve as a source of energy and form the structural foundation of all membranes, but have also emerged as mediators that not only impact classical oncogenic signaling pathways, but also contribute to melanoma progression. Various alterations in fatty acid metabolism have been reported and can contribute to melanoma cell aggressiveness. Elevated expression of the key lipogenic fatty acid synthase is associated with tumor cell invasion and poor prognosis. Fatty acid uptake from the surrounding microenvironment, fatty acid β-oxidation and storage also appear to play an essential role in tumor cell migration. The aim of this review is (i) to focus on the major alterations affecting lipid storage organelles and lipid metabolism. A particular attention has been paid to glycerophospholipids, sphingolipids, sterols and eicosanoids, (ii) to discuss how these metabolic dysregulations contribute to the phenotype plasticity of melanoma cells and/or melanoma aggressiveness, and (iii) to highlight therapeutic approaches targeting lipid metabolism that could be applicable for melanoma treatment. Full article
(This article belongs to the Special Issue Cellular Differentiation in Melanoma Development)
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19 pages, 992 KiB  
Review
Insights into Differentiation of Melanocytes from Human Stem Cells and Their Relevance for Melanoma Treatment
by Madalina A. Mirea, Stefan Eckensperger, Markus Hengstschläger and Mario Mikula
Cancers 2020, 12(9), 2508; https://doi.org/10.3390/cancers12092508 - 3 Sep 2020
Cited by 8 | Viewed by 5274
Abstract
Malignant melanoma represents a highly aggressive form of skin cancer. The metastatic process itself is mostly governed by the so-called epithelial mesenchymal transition (EMT), which confers cancer cells migrative, invasive and resistance abilities. Since EMT represents a conserved developmental process, it is worthwhile [...] Read more.
Malignant melanoma represents a highly aggressive form of skin cancer. The metastatic process itself is mostly governed by the so-called epithelial mesenchymal transition (EMT), which confers cancer cells migrative, invasive and resistance abilities. Since EMT represents a conserved developmental process, it is worthwhile further examining the nature of early developmental steps fundamental for melanocyte differentiation. This can be done either in vivo by analyzing the physiologic embryo development in different species or by in vitro studies of melanocytic differentiation originating from embryonic human stem cells. Most importantly, external cues drive progenitor cell differentiation, which can be divided in stages favoring neural crest specification or melanocytic differentiation and proliferation. In this review, we describe ectopic factors which drive human pluripotent stem cell differentiation to melanocytes in 2D, as well as in organoid models. Furthermore, we compare developmental mechanisms with processes described to occur during melanoma development. Finally, we suggest differentiation factors as potential co-treatment options for metastatic melanoma patients. Full article
(This article belongs to the Special Issue Cellular Differentiation in Melanoma Development)
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19 pages, 2483 KiB  
Review
Decoding the Role of CD271 in Melanoma
by Anna Vidal and Torben Redmer
Cancers 2020, 12(9), 2460; https://doi.org/10.3390/cancers12092460 - 31 Aug 2020
Cited by 19 | Viewed by 5580
Abstract
The evolution of melanoma, the most aggressive type of skin cancer, is triggered by driver mutations that are acquired in the coding regions of particularly BRAF (rat fibrosarcoma serine/threonine kinase, isoform B) or NRAS (neuroblastoma-type ras sarcoma virus) in melanocytes. Although driver mutations [...] Read more.
The evolution of melanoma, the most aggressive type of skin cancer, is triggered by driver mutations that are acquired in the coding regions of particularly BRAF (rat fibrosarcoma serine/threonine kinase, isoform B) or NRAS (neuroblastoma-type ras sarcoma virus) in melanocytes. Although driver mutations strongly determine tumor progression, additional factors are likely required and prerequisite for melanoma formation. Melanocytes are formed during vertebrate development in a well-controlled differentiation process of multipotent neural crest stem cells (NCSCs). However, mechanisms determining the properties of melanocytes and melanoma cells are still not well understood. The nerve growth factor receptor CD271 is likewise expressed in melanocytes, melanoma cells and NCSCs and programs the maintenance of a stem-like and migratory phenotype via a comprehensive network of associated genes. Moreover, CD271 regulates phenotype switching, a process that enables the rapid and reversible conversion of proliferative into invasive or non-stem-like states into stem-like states by yet largely unknown mechanisms. Here, we summarize current findings about CD271-associated mechanisms in melanoma cells and illustrate the role of CD271 for melanoma cell migration and metastasis, phenotype-switching, resistance to therapeutic interventions, and the maintenance of an NCSC-like state. Full article
(This article belongs to the Special Issue Cellular Differentiation in Melanoma Development)
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25 pages, 2182 KiB  
Review
Intrinsic Balance between ZEB Family Members Is Important for Melanocyte Homeostasis and Melanoma Progression
by Kenneth Bruneel, Jeroen Verstappe, Niels Vandamme and Geert Berx
Cancers 2020, 12(8), 2248; https://doi.org/10.3390/cancers12082248 - 11 Aug 2020
Cited by 21 | Viewed by 4209
Abstract
It has become clear that cellular plasticity is a main driver of cancer therapy resistance. Consequently, there is a need to mechanistically identify the factors driving this process. The transcription factors of the zinc-finger E-box-binding homeobox family, consisting of ZEB1 and ZEB2, are [...] Read more.
It has become clear that cellular plasticity is a main driver of cancer therapy resistance. Consequently, there is a need to mechanistically identify the factors driving this process. The transcription factors of the zinc-finger E-box-binding homeobox family, consisting of ZEB1 and ZEB2, are notorious for their roles in epithelial-to-mesenchymal transition (EMT). However, in melanoma, an intrinsic balance between ZEB1 and ZEB2 seems to determine the cellular state by modulating the expression of the master regulator of melanocyte homeostasis, microphthalmia-associated transcription factor (MITF). ZEB2 drives MITF expression and is associated with a differentiated/proliferative melanoma cell state. On the other hand, ZEB1 is correlated with low MITF expression and a more invasive, stem cell-like and therapy-resistant cell state. This intrinsic balance between ZEB1 and ZEB2 could prove to be a promising therapeutic target for melanoma patients. In this review, we will summarise what is known on the functional mechanisms of these transcription factors. Moreover, we will look specifically at their roles during melanocyte-lineage development and homeostasis. Finally, we will overview the current literature on ZEB1 and ZEB2 in the melanoma context and link this to the ‘phenotype-switching’ model of melanoma cellular plasticity. Full article
(This article belongs to the Special Issue Cellular Differentiation in Melanoma Development)
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17 pages, 1293 KiB  
Review
EMT-Inducing Transcription Factors, Drivers of Melanoma Phenotype Switching, and Resistance to Treatment
by Yaqi Tang, Simon Durand, Stéphane Dalle and Julie Caramel
Cancers 2020, 12(8), 2154; https://doi.org/10.3390/cancers12082154 - 4 Aug 2020
Cited by 53 | Viewed by 6585
Abstract
Transcription factors, extensively described for their role in epithelial–mesenchymal transition (EMT-TFs) in epithelial cells, also display essential functions in the melanocyte lineage. Recent evidence has shown specific expression patterns and functions of these EMT-TFs in neural crest-derived melanoma compared to carcinoma. Herein, we [...] Read more.
Transcription factors, extensively described for their role in epithelial–mesenchymal transition (EMT-TFs) in epithelial cells, also display essential functions in the melanocyte lineage. Recent evidence has shown specific expression patterns and functions of these EMT-TFs in neural crest-derived melanoma compared to carcinoma. Herein, we present an update of the specific roles of EMT-TFs in melanocyte differentiation and melanoma progression. As major regulators of phenotype switching between differentiated/proliferative and neural crest stem cell-like/invasive states, these factors appear as major drivers of intra-tumor heterogeneity and resistance to treatment in melanoma, which opens new avenues in terms of therapeutic targeting. Full article
(This article belongs to the Special Issue Cellular Differentiation in Melanoma Development)
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