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Cancers
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Metastatic Melanoma: From Gene Profiling to Targeted Therapy
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Metastatic Melanoma: From Gene Profiling to Targeted Therapy

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

Deadline for manuscript submissions: closed (15 June 2024) | Viewed by 10605

Special Issue Editors

Dr. Llucia Alos

E-Mail Website
Guest Editor
Pathology Department, Hospital Clinic, Universidad de Barcelona, 08036 Barcelona, Spain
Interests: molecular pathology; melanoma
Dr. Cristina Teixidó

E-Mail Website
Guest Editor
Translational Genomic and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
Interests: biomarker; lung cancer; molecular pathology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The development and progression of melanoma is a consequence of an uncontrolled cell growth due to a combination of genetic alterations that lead to neoplastic transformation and the escape from inhibitory signals.  Several key molecular pathways have been associated with the onset, proliferation, survival, progression, and invasion of melanoma. The most important oncogenic pathway is the mitogen-activated protein kinase (MAPK), but additional pathways, such as PI3K-AKT and NFκB, have been associated with melanoma development and progression.

In addition to the genetic alterations of tumor cells that lead to cell proliferation, a regulatory role has been attributed to the tumor microenvironment (TME), which in turn is regulated by the gene profile. The TME interacts with the host’s immune system and plays important roles in tumor progression, immune escape, and metastasis.

The progressive understanding of melanoma molecular pathways and TME regulation has enabled the development of successful targeted therapies and immunotherapies for unresectable stage III and IV melanoma.

Targeting the MAPK signaling pathway, as well as tumor immune checkpoint inhibitors are useful treatments, but often show drug resistance. To avoid resistance, combination treatments have been and are being studied continuously.

An increased understanding of the role of genes and proteins in key signaling pathways in melanoma progression is needed for more effective treatments.

This Special Issue will highlight the role of genetic alterations in melanoma cells and TME regulation, covering both basic and translational aspects that advance our understanding in order to find therapies for melanoma.

In this Special Issue, original research articles and reviews are welcome.

We look forward to receiving your contributions.

Dr. Llucia Alos
Dr. Cristina Teixidó
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 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
  • MAPK
  • MEK
  • BRAF
  • target therapy
  • immunotherapy
  • CTL-1
  • PD-L1
  • tumor microenvironment

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Published Papers (5 papers)

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Research

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17 pages, 2545 KiB  
Article
Impact of Genomic Mutation on Melanoma Immune Microenvironment and IFN-1 Pathway-Driven Therapeutic Responses
by Fátima María Mentucci, Elisa Ayelén Romero Nuñez, Agustina Ercole, Valentina Silvetti, Jessica Dal Col and María Julia Lamberti
Cancers 2024, 16(14), 2568; https://doi.org/10.3390/cancers16142568 - 17 Jul 2024
Viewed by 1195
Abstract
The BRAFV600E mutation, found in approximately 50% of melanoma cases, plays a crucial role in the activation of the MAPK/ERK signaling pathway, which promotes tumor cell proliferation. This study aimed to evaluate its impact on the melanoma immune microenvironment and therapeutic responses, particularly [...] Read more.
The BRAFV600E mutation, found in approximately 50% of melanoma cases, plays a crucial role in the activation of the MAPK/ERK signaling pathway, which promotes tumor cell proliferation. This study aimed to evaluate its impact on the melanoma immune microenvironment and therapeutic responses, particularly focusing on immunogenic cell death (ICD), a pivotal cytotoxic process triggering anti-tumor immune responses. Through comprehensive in silico analysis of the Cancer Genome Atlas data, we explored the association between the BRAFV600E mutation, immune subtype dynamics, and tumor mutation burden (TMB). Our findings revealed that the mutation correlated with a lower TMB, indicating a reduced generation of immunogenic neoantigens. Investigation into immune subtypes reveals an exacerbation of immunosuppression mechanisms in BRAFV600E-mutated tumors. To assess the response to ICD inducers, including doxorubicin and Me-ALA-based photodynamic therapy (PDT), compared to the non-ICD inducer cisplatin, we used distinct melanoma cell lines with wild-type BRAF (SK-MEL-2) and BRAFV600E mutation (SK-MEL-28, A375). We demonstrated a differential response to PDT between the WT and BRAFV600E cell lines. Further transcriptomic analysis revealed upregulation of IFNAR1, IFNAR2, and CXCL10 genes associated with the BRAFV600E mutation, suggesting their involvement in ICD. Using a gene reporter assay, we showed that PDT robustly activated the IFN-1 pathway through cGAS-STING signaling. Collectively, our results underscore the complex interplay between the BRAFV600E mutation and immune responses, suggesting a putative correlation between tumors carrying the mutation and their responsiveness to therapies inducing the IFN-1 pathway, such as the ICD inducer PDT, possibly mediated by the elevated expression of IFNAR1/2 receptors Full article
(This article belongs to the Special Issue Metastatic Melanoma: From Gene Profiling to Targeted Therapy)
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15 pages, 5666 KiB  
Article
The Clinical, Genomic, and Transcriptomic Landscape of BRAF Mutant Cancers
by Suzanne Kazandjian, Emmanuelle Rousselle, Matthew Dankner, David W. Cescon, Anna Spreafico, Kim Ma, Petr Kavan, Gerald Batist and April A. N. Rose
Cancers 2024, 16(2), 445; https://doi.org/10.3390/cancers16020445 - 19 Jan 2024
Cited by 3 | Viewed by 2742
Abstract
Background: BRAF mutations are classified into four molecularly distinct groups, and Class 1 (V600) mutant tumors are treated with targeted therapies. Effective treatment has not been established for Class 2/3 or BRAF Fusions. We investigated whether BRAF mutation class differed according to clinical, [...] Read more.
Background: BRAF mutations are classified into four molecularly distinct groups, and Class 1 (V600) mutant tumors are treated with targeted therapies. Effective treatment has not been established for Class 2/3 or BRAF Fusions. We investigated whether BRAF mutation class differed according to clinical, genomic, and transcriptomic variables in cancer patients. Methods: Using the AACR GENIE (v.12) cancer database, the distribution of BRAF mutation class in adult cancer patients was analyzed according to sex, age, primary race, and tumor type. Genomic alteration data and transcriptomic analysis was performed using The Cancer Genome Atlas. Results: BRAF mutations were identified in 9515 (6.2%) samples among 153,834, with melanoma (31%), CRC (20.7%), and NSCLC (13.9%) being the most frequent cancer types. Class 1 harbored co-mutations outside of the MAPK pathway (TERT, RFN43) vs. Class 2/3 mutations (RAS, NF1). Across all tumor types, Class 2/3 were enriched for alterations in genes involved in UV response and WNT/β-catenin. Pathway analysis revealed enrichment of WNT/β-catenin and Hedgehog signaling in non-V600 mutated CRC. Males had a higher proportion of Class 3 mutations vs. females (17.4% vs. 12.3% q = 0.003). Non-V600 mutations were generally more common in older patients (aged 60+) vs. younger (38% vs. 15% p < 0.0001), except in CRC (15% vs. 30% q = 0.0001). Black race was associated with non-V600 BRAF alterations (OR: 1.58; p < 0.0001). Conclusions: Class 2/3 BRAFs are more present in Black male patients with co-mutations outside of the MAPK pathway, likely requiring additional oncogenic input for tumorigenesis. Improving access to NGS and trial enrollment will help the development of targeted therapies for non-V600 BRAF mutations. Full article
(This article belongs to the Special Issue Metastatic Melanoma: From Gene Profiling to Targeted Therapy)
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13 pages, 300 KiB  
Article
The Driverless Triple-Wild-Type (BRAF, RAS, KIT) Cutaneous Melanoma: Whole Genome Sequencing Discoveries
by Orsolya Pipek, Laura Vizkeleti, Viktória Doma, Donát Alpár, Csaba Bödör, Sarolta Kárpáti and Jozsef Timar
Cancers 2023, 15(6), 1712; https://doi.org/10.3390/cancers15061712 - 10 Mar 2023
Cited by 5 | Viewed by 2330
Abstract
The genetic makeup of the triple-wild-type melanoma (BRAF, NRAS and NF1) has been known for some time, but those studies grouped together rare histopathological versions with common ones, as well as mucosal and even uveal ones. Here we used whole genome sequencing to [...] Read more.
The genetic makeup of the triple-wild-type melanoma (BRAF, NRAS and NF1) has been known for some time, but those studies grouped together rare histopathological versions with common ones, as well as mucosal and even uveal ones. Here we used whole genome sequencing to genetically characterize the triple-wild-type melanoma (TWM), termed here as BRAF, RAS and KIT wild type (the most frequent oncogenic drivers of skin melanoma), using the most common histological forms and excluding rare ones. All these tumors except one were clearly induced by UV based on the mutational signature. The tumor mutational burden was low in TWM, except in the NF1 mutant forms, and a relatively high frequency of elevated LOH scores suggested frequent homologue recombination deficiency, but this was only confirmed by the mutation signature in one case. Furthermore, all these TWMs were microsatellite-stabile. In this driverless setting, we revealed rare oncogenic drivers known from melanoma or other cancer types and identified rare actionable tyrosine kinase mutations in NTRK1, RET and VEGFR1. Mutations of TWM identified genes involved in antitumor immunity (negative and positive predictors of immunotherapy), Ca++ and BMP signaling. The two regressed melanomas of this cohort shared a 17-gene mutation signature, containing genes involved in antitumor immunity and several cell surface receptors. Even with this comprehensive genomic approach, a few cases remained driverless, suggesting that unrecognized drivers are hiding among passenger mutations. Full article
(This article belongs to the Special Issue Metastatic Melanoma: From Gene Profiling to Targeted Therapy)

Review

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18 pages, 2212 KiB  
Review
Need for a Dedicated Ophthalmic Malignancy Clinico-Biological Biobank: The Nice Ocular MAlignancy (NOMA) Biobank
by Arnaud Martel, Lauris Gastaud, Christelle Bonnetaud, Sacha Nahon-Esteve, Kevin Washetine, Olivier Bordone, Myriam Salah, Virginie Tanga, Julien Fayada, Virginie Lespinet, Maryline Allegra, Salome Lalvee, Katia Zahaf, Stephanie Baillif, Corine Bertolotto, Baharia Mograbi, Sandra Lassalle and Paul Hofman
Cancers 2023, 15(8), 2372; https://doi.org/10.3390/cancers15082372 - 19 Apr 2023
Cited by 3 | Viewed by 1641
Abstract
Ophthalmic malignancies include various rare neoplasms involving the conjunctiva, the uvea, or the periocular area. These tumors are characterized by their scarcity as well as their histological, and sometimes genetic, diversity. Uveal melanoma (UM) is the most common primary intraocular malignancy. UM raises [...] Read more.
Ophthalmic malignancies include various rare neoplasms involving the conjunctiva, the uvea, or the periocular area. These tumors are characterized by their scarcity as well as their histological, and sometimes genetic, diversity. Uveal melanoma (UM) is the most common primary intraocular malignancy. UM raises three main challenges highlighting the specificity of ophthalmic malignancies. First, UM is a very rare malignancy with an estimated incidence of 6 cases per million inhabitants. Second, tissue biopsy is not routinely recommended due to the risk of extraocular dissemination. Third, UM is an aggressive cancer because it is estimated that about 50% of patients will experience metastatic spread without any curative treatment available at this stage. These challenges better explain the two main objectives in the creation of a dedicated UM biobank. First, collecting UM samples is essential due to tissue scarcity. Second, large-scale translational research programs based on stored human samples will help to better determine UM pathogenesis with the aim of identifying new biomarkers, allowing for early diagnosis and new targeted treatment modalities. Other periocular malignancies, such as conjunctival melanomas or orbital malignancies, also raise specific concerns. In this context, the number of biobanks worldwide dedicated to ocular malignancies is very limited. The aims of this article were (i) to describe the specific challenges raised by a dedicated ocular malignancy biobank, (ii) to report our experience in setting up such a biobank, and (iii) to discuss future perspectives in this field. Full article
(This article belongs to the Special Issue Metastatic Melanoma: From Gene Profiling to Targeted Therapy)
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Other

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8 pages, 2078 KiB  
Perspective
The Emerging Burden of Genetic Instability and Mutation in Melanoma: Role of Molecular Mechanisms
by Rashidul Alam Mahumud and Md. Shahjalal
Cancers 2022, 14(24), 6202; https://doi.org/10.3390/cancers14246202 - 15 Dec 2022
Cited by 5 | Viewed by 1906
Abstract
Melanoma is a severe skin cancer affecting thousands of people and a growing public health concern worldwide. The potential hallmarks of melanoma are genetic instability and mutation (GIAM), which are driving mechanisms for phenotypic variation and adaptation in melanoma. In metastatic melanoma, DNA [...] Read more.
Melanoma is a severe skin cancer affecting thousands of people and a growing public health concern worldwide. The potential hallmarks of melanoma are genetic instability and mutation (GIAM), which are driving mechanisms for phenotypic variation and adaptation in melanoma. In metastatic melanoma, DNA repair-associated genes are frequently expressed at higher levels than in primary cancers, suggesting melanoma cells rely on genetic stability to spread distantly. The tumour microenvironment is affected by genomic instability and melanoma mutation (GIMM), which plays significant roles in developing GIMM and their contributions to the overall disease burden. The GIAM is the crucial vulnerability of cancer cells, determining their sensitivity to harmful treatments, including radiation and many chemotherapeutics. The high incidence of melanoma is typically associated with genetic modifications, and several clinical and genetic interventions have been critical in easing the burden. Full article
(This article belongs to the Special Issue Metastatic Melanoma: From Gene Profiling to Targeted Therapy)
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