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Cancers
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Molecular Mechanisms and Signaling Pathways in Melanoma
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Molecular Mechanisms and Signaling Pathways in Melanoma

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (20 March 2023) | Viewed by 12733

Special Issue Editors

Dr. Alessio Giubellino

E-Mail Website
Guest Editor
1. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
2. Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
Interests: dermatopathology; melanoma; receptor tyrosine kinase; met; hgf; histopathology
Special Issues, Collections and Topics in MDPI journals
Dr. Carlos Torres-Cabala

E-Mail Website
Guest Editor
MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA
Interests: cutaneous tumors; lymphomas; melanoma; pathology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alteration in signaling pathways is the prime mechanism of oncogenesis in the development of several cancers. In melanoma, these mechanisms are reflected in mutations in genes involved in several signaling pathways, such as the one leading to activation of the mitogen-activated protein kinase (MAPK) cascade. This important pathogenic molecular pathway includes alterations in BRAF, NRAS, KIT, and NF1. Pathways involved in cell cycle progression, including CDKN2A, RB protein, cyclin D1, and CDK4/6, are also widely involved in melanoma pathogenesis. Molecular analysis has revealed different drivers in different subtypes of melanoma. The discovery of these drivers and related molecular pathways has afforded the opportunity to develop life-changing therapeutics, as exemplified by the adoption of BRAF and MEK inhibitors as standard of care for melanoma, in addition to immunotherapy. However, resistance to these therapeutic regimens ensues in a large portion of patients that initially respond, leading to an unmet need for novel and more durable therapies.

This Special Issue explores known and emerging molecular mechanisms and signaling pathways in the development and progression of melanoma, highlighting the opportunity for future development of novel drugs and drug combinations for the personalized care of melanoma patients.

Dr. Alessio Giubellino
Dr. Carlos Torres-Cabala
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. 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

  • melanoma
  • signaling pathways
  • MAPK
  • BRAF
  • NRAS
  • CDKN2A
  • targeted therapy
  • BRAF inhibitors
  • MEK inhibitors

Published Papers (6 papers)

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Editorial

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2 pages, 173 KiB  
Editorial
Editorial for Special Issue “Molecular Mechanisms and Signaling Pathways in Melanoma”
by Alessio Giubellino and Carlos Torres-Cabala
Cancers 2023, 15(19), 4675; https://doi.org/10.3390/cancers15194675 - 22 Sep 2023
Cited by 1 | Viewed by 813
Abstract
Melanoma represents the leading cause of death from cutaneous malignancy [...] Full article
(This article belongs to the Special Issue Molecular Mechanisms and Signaling Pathways in Melanoma)

Research

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14 pages, 3397 KiB  
Article
MET Receptor Tyrosine Kinase Inhibition Reduces Interferon-Gamma (IFN-γ)-Stimulated PD-L1 Expression through the STAT3 Pathway in Melanoma Cells
by Kyu Young Song, Yong Hwan Han, Heidi Roehrich, Mary E. Brown, Carlos Torres-Cabala and Alessio Giubellino
Cancers 2023, 15(13), 3408; https://doi.org/10.3390/cancers15133408 - 29 Jun 2023
Cited by 1 | Viewed by 1389
Abstract
Melanoma is the leading cause of death from cutaneous malignancy. While targeted therapy and immunotherapy with checkpoint inhibitors have significantly decreased the mortality rate of this disease, advanced melanoma remains a therapeutic challenge. Here, we confirmed that interferon-gamma (IFN-γ)-induced PD-L1 expression in melanoma [...] Read more.
Melanoma is the leading cause of death from cutaneous malignancy. While targeted therapy and immunotherapy with checkpoint inhibitors have significantly decreased the mortality rate of this disease, advanced melanoma remains a therapeutic challenge. Here, we confirmed that interferon-gamma (IFN-γ)-induced PD-L1 expression in melanoma cell lines. This increased expression was down-regulated by the reduction in phosphorylated STAT3 signaling via MET tyrosine kinase inhibitor treatment. Furthermore, immunoprecipitation and confocal immunofluorescence microscopy analysis reveals MET and PD-L1 protein–protein interaction and colocalization on the cell surface membrane of melanoma cells. Together, these findings demonstrate that the IFN-γ-induced PD-L1 expression in melanoma cells is negatively regulated by MET inhibition through the JAK/STAT3 signaling pathway and establish the colocalization and interaction between an RTK and a checkpoint protein in melanoma cells. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Signaling Pathways in Melanoma)
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0 pages, 8393 KiB  
Article
P38 Mediates Tumor Suppression through Reduced Autophagy and Actin Cytoskeleton Changes in NRAS-Mutant Melanoma
by Ishani Banik, Adhideb Ghosh, Erin Beebe, Blaž Burja, Mojca Frank Bertoncelj, Christopher M. Dooley, Enni Markkanen, Reinhard Dummer, Elisabeth M. Busch-Nentwich and Mitchell P. Levesque
Cancers 2023, 15(3), 877; https://doi.org/10.3390/cancers15030877 - 31 Jan 2023
Cited by 3 | Viewed by 2117
Abstract
Hotspot mutations in the NRAS gene are causative genetic events associated with the development of melanoma. Currently, there are no FDA-approved drugs directly targeting NRAS mutations. Previously, we showed that p38 acts as a tumor suppressor in vitro and in vivo with respect [...] Read more.
Hotspot mutations in the NRAS gene are causative genetic events associated with the development of melanoma. Currently, there are no FDA-approved drugs directly targeting NRAS mutations. Previously, we showed that p38 acts as a tumor suppressor in vitro and in vivo with respect to NRAS-mutant melanoma. We observed that because of p38 activation through treatment with the protein synthesis inhibitor, anisomycin leads to a transient upregulation of several targets of the cAMP pathway, representing a stressed cancer cell state that is often observed by therapeutic doses of MAPK inhibitors in melanoma patients. Meanwhile, genetically induced p38 or its stable transduction leads to a distinct cellular transcriptional state. Contrary to previous work showing an association of invasiveness with high p38 levels in BRAF-mutated melanoma, there was no correlation of p38 expression with NRAS-mutant melanoma invasion, highlighting the difference in BRAF and NRAS-driven melanomas. Although the role of p38 has been reported to be that of both tumor suppressor and oncogene, we show here that p38 specifically plays the role of a tumor suppressor in NRAS-mutant melanoma. Both the transient and stable activation of p38 elicits phosphorylation of mTOR, reported to be a master switch in regulating autophagy. Indeed, we observed a correlation between elevated levels of phosphorylated mTOR and a reduction in LC3 conversion (LCII/LCI), indicative of suppressed autophagy. Furthermore, a reduction in actin intensity in p38–high cells strongly suggests a role of mTOR in regulating actin and a remodeling in the NRAS-mutant melanoma cells. Therefore, p38 plays a tumor suppressive role in NRAS-mutant melanomas at least partially through the mechanism of mTOR upregulation, suppressed autophagy, and reduced actin polymerization. One or more combinations of MEK inhibitors with either anisomycin, rapamycin, chloroquine/bafilomycin, and cytochalasin modulate p38 activation, mTOR phosphorylation, autophagy, and actin polymerization, respectively, and they may provide an alternate route to targeting NRAS-mutant melanoma. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Signaling Pathways in Melanoma)
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20 pages, 9617 KiB  
Article
RNA-seq and ChIP-seq Identification of Unique and Overlapping Targets of GLI Transcription Factors in Melanoma Cell Lines
by Matea Kurtović, Nikolina Piteša, Nenad Bartoniček, Petar Ozretić, Vesna Musani, Josipa Čonkaš, Tina Petrić, Cecile King and Maja Sabol
Cancers 2022, 14(18), 4540; https://doi.org/10.3390/cancers14184540 - 19 Sep 2022
Cited by 4 | Viewed by 3219
Abstract
Background: Despite significant progress in therapy, melanoma still has a rising incidence worldwide, and novel treatment strategies are needed. Recently, researchers have recognized the involvement of the Hedgehog-GLI (HH-GLI) signaling pathway in melanoma and its consistent crosstalk with the MAPK pathway. In order [...] Read more.
Background: Despite significant progress in therapy, melanoma still has a rising incidence worldwide, and novel treatment strategies are needed. Recently, researchers have recognized the involvement of the Hedgehog-GLI (HH-GLI) signaling pathway in melanoma and its consistent crosstalk with the MAPK pathway. In order to further investigate the link between the two pathways and to find new target genes that could be considered for combination therapy, we set out to find transcriptional targets of all three GLI proteins in melanoma. Methods: We performed RNA sequencing on three melanoma cell lines (CHL-1, A375, and MEL224) with overexpressed GLI1, GLI2, and GLI3 and combined them with the results of ChIP-sequencing on endogenous GLI1, GLI2, and GLI3 proteins. After combining these results, 21 targets were selected for validation by qPCR. Results: RNA-seq revealed a total of 808 differentially expressed genes (DEGs) for GLI1, 941 DEGs for GLI2, and 58 DEGs for GLI3. ChIP-seq identified 527 genes that contained GLI1 binding sites in their promoters, 1103 for GLI2 and 553 for GLI3. A total of 15 of these targets were validated in the tested cell lines, 6 of which were detected by both RNA-seq and ChIP-seq. Conclusions: Our study provides insight into the unique and overlapping transcriptional output of the GLI proteins in melanoma. We suggest that our findings could provide new potential targets to consider while designing melanoma-targeted therapy. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Signaling Pathways in Melanoma)
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Review

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23 pages, 2231 KiB  
Review
Exosome-Derived microRNA: Implications in Melanoma Progression, Diagnosis and Treatment
by Qiang Ye, Zi Li, Yang Li, Yirong Li, Yan Zhang, Runlin Gui, Yue Cui, Qi Zhang, Lu Qian, Yuyan Xiong and Yi Yu
Cancers 2023, 15(1), 80; https://doi.org/10.3390/cancers15010080 - 23 Dec 2022
Cited by 8 | Viewed by 2240
Abstract
Melanoma is a malignant and aggressive cancer, and its progression is greatly affected by interactions between melanoma cells and their surroundings. Exploration on mechanism of melanoma and improved diagnostic and therapeutic strategies are becoming increasingly important. Unlike extracellular messengers that mainly work on [...] Read more.
Melanoma is a malignant and aggressive cancer, and its progression is greatly affected by interactions between melanoma cells and their surroundings. Exploration on mechanism of melanoma and improved diagnostic and therapeutic strategies are becoming increasingly important. Unlike extracellular messengers that mainly work on targeted cells through corresponding receptors, exosomes are essential intercellular messengers that deliver biologically active substances such as nucleic acids and proteins to target cells for cell–cell communication. Of them, microRNAs (miRNAs) are common and important exosomal components that can regulate the expression of a wide range of target genes. Accordingly, exosome-derived miRNAs play a significant role in melanoma progression, including invasion and metastasis, microenvironment establishment, angiogenesis, and immune escape. MiRNA signatures of exosomes are specific in melanoma patients compared to healthy controls, thus circulating miRNAs, especially exosomal miRNAs, become potential diagnostic markers and therapeutic targets for melanoma. This review aims to summarize recent studies on the role of exosomal miRNAs in melanoma as well as ongoing efforts in melanoma treatment. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Signaling Pathways in Melanoma)
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17 pages, 1021 KiB  
Review
New Insights into the Phenotype Switching of Melanoma
by Chiara Pagliuca, Luca Di Leo and Daniela De Zio
Cancers 2022, 14(24), 6118; https://doi.org/10.3390/cancers14246118 - 12 Dec 2022
Cited by 7 | Viewed by 2322
Abstract
Melanoma is considered one of the deadliest skin cancers, partly because of acquired resistance to standard therapies. The most recognized driver of resistance relies on acquired melanoma cell plasticity, or the ability to dynamically switch among differentiation phenotypes. This confers the tumor noticeable [...] Read more.
Melanoma is considered one of the deadliest skin cancers, partly because of acquired resistance to standard therapies. The most recognized driver of resistance relies on acquired melanoma cell plasticity, or the ability to dynamically switch among differentiation phenotypes. This confers the tumor noticeable advantages. During the last year, two new features have been included in the hallmarks of cancer, namely “Unlocking phenotypic plasticity” and “Non-mutational epigenetic reprogramming”. Such are inextricably intertwined as, most of the time, plasticity is not discernable at the genetic level, as it rather consists of epigenetic reprogramming heavily influenced by external factors. By analyzing current literature, this review provides reasoning about the origin of plasticity and clarifies whether such features already exist among tumors or are acquired by selection. Moreover, markers of plasticity, molecular effectors, and related tumor advantages in melanoma will be explored. Ultimately, as this new branch of tumor biology opened a wide landscape of therapeutic possibilities, in the final paragraph of this review, we will focus on newly characterized drugs targeting melanoma plasticity. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Signaling Pathways in Melanoma)
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