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Cancers
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Melanoma: Pathology and Translational Research
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Melanoma: Pathology and Translational Research

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

Deadline for manuscript submissions: closed (20 April 2024) | Viewed by 4964

Special Issue Editors

Dr. Alessio Giubellino

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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
Dr. Jose A. Plaza

E-Mail Website
Guest Editor
Department of Pathology and Dermatology, The Ohio State University Wexner Medical Center (OSUWMC), Columbus, OH 43221, USA
Interests: pigmented skin lesions; adnexal skin neoplasms; immunohistochemistry in cutaneous tumors

Special Issue Information

Dear Colleagues,

We are excited to announce a Special Issue of Cancers, “Melanoma: Pathology and Translational Research”, dedicated to advancing our understanding of melanoma through the lens of pathology and translational research. Melanoma is a challenging malignancy, and insights from both the laboratory and clinical research are essential to driving progress in diagnosis and treatment.

This Special Issue aims to showcase the latest developments in the field of melanoma research, with a specific focus on how pathology and translational research intersect. We invite original research articles and reviews exploring various aspects of melanoma, including the histopathologic characterization of melanoma subtypes, the molecular and genetic profiling of melanoma, the identification of prognostic and predictive biomarkers, innovative diagnostic approaches, translational studies, and the use of novel technologies like digital pathology and artificial intelligence in the assessment of melanoma.

This Special Issue offers a unique opportunity to contribute to the advancement of melanoma research. We encourage researchers, clinicians, and pathologists to submit their work and help shape the future of melanoma diagnosis and treatment.

Dr. Alessio Giubellino
Dr. Carlos Torres-Cabala
Dr. Jose A. Plaza
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
  • histopathology
  • dermatopathology
  • molecular profiling
  • biomarkers
  • digital pathology
  • translational studies
  • cancer therapy

Published Papers (6 papers)

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Research

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14 pages, 2199 KiB  
Article
The Role of T-Cadherin (CDH13) in Treatment Options with Garcinol in Melanoma
by Sebastian Staebler, Sebastian Hoechst, Aranya Thongmao, Nadja Schneider, Anja-Katrin Bosserhoff and Silke Kuphal
Cancers 2024, 16(10), 1853; https://doi.org/10.3390/cancers16101853 - 12 May 2024
Viewed by 387
Abstract
Targeted therapies with chemotherapeutic agents and immunotherapy with checkpoint inhibitors are among the systemic therapies recommended in the guidelines for clinicians to treat melanoma. Although there have been constant improvements in the treatment of melanoma, resistance to the established therapies continues to occur. [...] Read more.
Targeted therapies with chemotherapeutic agents and immunotherapy with checkpoint inhibitors are among the systemic therapies recommended in the guidelines for clinicians to treat melanoma. Although there have been constant improvements in the treatment of melanoma, resistance to the established therapies continues to occur. Therefore, the purpose of this study was to explore the function of garcinol with regards to specific cancer properties such as proliferation and apoptosis. Garcinol, a natural compound isolated from the plant also known as mangosteen (Garcinia mangostana), is a newly discovered option for cancer treatment. Numerous pharmaceutical substances are derived from plants. For example, the derivates of camptothecin, extracted from the bark of the Chinese tree of happiness (Camptotheca acuminate), or paclitaxel, extracted from the bark of the Western yew tree (Taxus brevifolia), are used as anti-cancer drugs. Here, we show that garcinol reduced proliferation and induced apoptosis in melanoma cell lines. In addition, we found that those cells that are positive for the expression of the cell–cell adhesion molecule T-cadherin (CDH13) respond more sensitively to treatment with garcinol. After knock-down experiments with an siRNA pool against T-cadherin, the sensitivity to garcinol decreased and proliferation and anti-apoptotic behavior of the cells was restored. We conclude that patients who are T-cadherin-positive could especially benefit from a therapy with garcinol. Full article
(This article belongs to the Special Issue Melanoma: Pathology and Translational Research)
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13 pages, 1536 KiB  
Article
Gene Expression Profile of Benign, Intermediate, and Malignant Spitz and Spitzoid Melanocytic Lesions
by Alessio Giubellino, Yuyu He, Sarah A. Munro, Yan Zhou, Kyu Young Song, Jose A. Plaza, Carlos A. Torres-Cabala and Andrew C. Nelson
Cancers 2024, 16(10), 1798; https://doi.org/10.3390/cancers16101798 - 8 May 2024
Viewed by 299
Abstract
Spitz and Spitzoid lesions represent one of the most challenging melanocytic neoplasms in dermatopathology. Nosologic classification has been more recently improved by the discovery of novel molecular drivers, particularly translocations. In the current study, we aimed to use an unbiased approach to explore [...] Read more.
Spitz and Spitzoid lesions represent one of the most challenging melanocytic neoplasms in dermatopathology. Nosologic classification has been more recently improved by the discovery of novel molecular drivers, particularly translocations. In the current study, we aimed to use an unbiased approach to explore the gene expression profile of a group of melanocytic Spitz and Spitzoid melanocytic lesions ranging from benign lesions to melanoma, including intermediate lesions such as SPARK nevi and atypical Spitz tumors/melanocytomas. Using unsupervised analysis of gene expression data, we found some distinct hierarchical clusters of lesions, including groups characterized by ALK and NTRK translocations. Few non-ALK translocated tumors demonstrated increased ALK expression, confirmed by immunohistochemistry. Spitz tumors with overlapping features of dysplastic nevi, so-called SPARK nevi, appear to have a common gene expression profile by hierarchical clustering. Finally, weighted gene correlation network analysis identified gene modules variably regulated in subtypes of these cases. Thus, gene expression profiling of Spitz and Spitzoid lesions represents a viable instrument for the characterization of these lesions. Full article
(This article belongs to the Special Issue Melanoma: Pathology and Translational Research)
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28 pages, 2643 KiB  
Article
Susceptibility of Melanoma Cells to Targeted Therapy Correlates with Protection by Blood Neutrophils
by Simone Wendlinger, Jonas Wohlfarth, Claudia Siedel, Sophia Kreft, Teresa Kilian, Sarah Junker, Luisa Schmid, Tobias Sinnberg, Ulrich Dischinger, Markus V. Heppt, Kilian Wistuba-Hamprecht, Friedegund Meier, Luise Erpenbeck, Elsa Neubert, Matthias Goebeler, Anja Gesierich, David Schrama, Corinna Kosnopfel and Bastian Schilling
Cancers 2024, 16(9), 1767; https://doi.org/10.3390/cancers16091767 - 2 May 2024
Viewed by 609
Abstract
Elevated levels of peripheral blood and tumor tissue neutrophils are associated with poorer clinical response and therapy resistance in melanoma. The underlying mechanism and the role of neutrophils in targeted therapy is still not fully understood. Serum samples of patients with advanced melanoma [...] Read more.
Elevated levels of peripheral blood and tumor tissue neutrophils are associated with poorer clinical response and therapy resistance in melanoma. The underlying mechanism and the role of neutrophils in targeted therapy is still not fully understood. Serum samples of patients with advanced melanoma were collected and neutrophil-associated serum markers were measured and correlated with response to targeted therapy. Blood neutrophils from healthy donors and patients with advanced melanoma were isolated, and their phenotypes, as well as their in vitro functions, were compared. In vitro functional tests were conducted through nonadherent cocultures with melanoma cells. Protection of melanoma cell lines by neutrophils was assessed under MAPK inhibition. Blood neutrophils from advanced melanoma patients exhibited lower CD16 expression compared to healthy donors. In vitro, both healthy-donor- and patient-derived neutrophils prevented melanoma cell apoptosis upon dual MAPK inhibition. The effect depended on cell–cell contact and melanoma cell susceptibility to treatment. Interference with protease activity of neutrophils prevented melanoma cell protection during treatment in cocultures. The negative correlation between neutrophils and melanoma outcomes seems to be linked to a protumoral function of neutrophils. In vitro, neutrophils exert a direct protective effect on melanoma cells during dual MAPK inhibition. This study further hints at a crucial role of neutrophil-related protease activity in protection. Full article
(This article belongs to the Special Issue Melanoma: Pathology and Translational Research)
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12 pages, 6647 KiB  
Article
PRAME Is an Effective Tool for the Diagnosis of Nevus-Associated Cutaneous Melanoma
by Andrea Ronchi, Gerardo Cazzato, Giuseppe Ingravallo, Giuseppe D’Abbronzo, Giuseppe Argenziano, Elvira Moscarella, Gabriella Brancaccio and Renato Franco
Cancers 2024, 16(2), 278; https://doi.org/10.3390/cancers16020278 - 9 Jan 2024
Viewed by 1336
Abstract
(1) Background: Nevus-associated cutaneous melanoma (CM) is relatively common in the clinical practice of dermatopathologists. The correct diagnosis and staging of nevus-associated cutaneous melanoma (CM) mainly relies on the correct discrimination between benign and malignant cells. Recently, PRAME has emerged as a promising [...] Read more.
(1) Background: Nevus-associated cutaneous melanoma (CM) is relatively common in the clinical practice of dermatopathologists. The correct diagnosis and staging of nevus-associated cutaneous melanoma (CM) mainly relies on the correct discrimination between benign and malignant cells. Recently, PRAME has emerged as a promising immunohistochemical marker of malignant melanocytes. (2) Methods: PRAME immunohistochemistry (IHC) was performed in 69 cases of nevus-associated CMs. Its expression was evaluated using a score ranging from 0 to 4+ based on the percentage of melanocytic cells with a nuclear expression. PRAME IHC sensitivity, specificity, positive predictive values, and negative predictive values were assessed. Furthermore, the agreement between morphological data and PRAME expression was evaluated for the diagnosis of melanoma components and nevus components. (3) Results: PRAME IHC showed a sensitivity of 59%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 71%. The diagnostic agreement between morphology and PRAME IHC was fair (Cohen’s Kappa: 0.3); the diagnostic agreement regarding the benign nevus components associated with CM was perfect (Cohen’s Kappa: 1.0). PRAME was significantly more expressed in thick invasive CMs than in thin cases (p = 0.02). (4) Conclusions: PRAME IHC should be considered for the diagnostic evaluation of nevus-associated CM and is most useful in cases of thick melanomas. Pathologists should carefully consider that a PRAME-positive cellular population within the context of a nevus could indicate a CM associated with the nevus. A negative result does not rule out this possibility. Full article
(This article belongs to the Special Issue Melanoma: Pathology and Translational Research)
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12 pages, 6735 KiB  
Article
Significant and Various Effects of ML329-Induced MITF Suppression in the Melanoma Cell Line
by Nami Nishikiori, Megumi Watanabe, Tatsuya Sato, Masato Furuhashi, Masae Okura, Tokimasa Hida, Hisashi Uhara and Hiroshi Ohguro
Cancers 2024, 16(2), 263; https://doi.org/10.3390/cancers16020263 - 7 Jan 2024
Cited by 1 | Viewed by 926
Abstract
To study the inhibitory effects on microphthalmia-associated transcription factor (MITF)-related biological aspects in malignant melanomas (MMs) in the presence or absence of the low-molecular MITF specific inhibitor ML329, cell viability, cellular metabolic functions, and three-dimensional (3D) spheroid formation efficacy were compared among MM [...] Read more.
To study the inhibitory effects on microphthalmia-associated transcription factor (MITF)-related biological aspects in malignant melanomas (MMs) in the presence or absence of the low-molecular MITF specific inhibitor ML329, cell viability, cellular metabolic functions, and three-dimensional (3D) spheroid formation efficacy were compared among MM cell lines including SK-mel-24, A375, dabrafenib- and trametinib-resistant A375 (A375DT), and WM266-4. Upon exposure to 2 or 10 μM of ML329, cell viability was significantly decreased in WM266-4, SK-mel-24, and A375DT cells, but not A375 cells, in a dose-dependent manner, and these toxic effects of ML329 were most evident in WM266-4 cells. Extracellular flux assays conducted using a Seahorse bioanalyzer revealed that treatment with ML329 increased basal respiration, ATP-linked respiration, proton leakage, and non-mitochondrial respiration in WM266-4 cells and decreased glycolytic function in SK-mel-24 cells, whereas there were no marked effects of ML329 on A375 and A375DT cells. A glycolytic stress assay under conditions of high glucose concentrations also demonstrated that the inhibitory effect of ML329 on the glycolytic function of WM266-4 cells was dose-dependent. In addition, ML329 significantly decreased 3D-spheroid-forming ability, though the effects of ML329 were variable among the MM cell lines. Furthermore, the mRNA expression levels of selected genes, including STAT3 as a possible regulator of 3D spheroid formation, KRAS and SOX2 as oncogenic-signaling-related factors, PCG1a as the main regulator of mitochondrial biogenesis, and HIF1a as a major hypoxia transcriptional regulator, fluctuated among the MM cell lines, possibly supporting the diverse ML329 effects mentioned above. The findings of diverse ML329 effects on various MM cell lines suggest that MITF-associated biological activities are different among various types of MM. Full article
(This article belongs to the Special Issue Melanoma: Pathology and Translational Research)
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Review

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17 pages, 4189 KiB  
Review
Spitz Tumors and Melanoma in the Genomic Age: A Retrospective Look at Ackerman’s Conundrum
by Carmelo Urso
Cancers 2023, 15(24), 5834; https://doi.org/10.3390/cancers15245834 - 14 Dec 2023
Viewed by 972
Abstract
After 25 years, “Ackerman’s conundrum”, namely, the distinction of benign from malignant Spitz neoplasms, remains challenging. Genomic studies have shown that most Spitz tumors harbor tyrosine and serine/threonine kinase fusions, including ALK, ROS1, NTRK1, NTRK2, NTRK3, BRAF and [...] Read more.
After 25 years, “Ackerman’s conundrum”, namely, the distinction of benign from malignant Spitz neoplasms, remains challenging. Genomic studies have shown that most Spitz tumors harbor tyrosine and serine/threonine kinase fusions, including ALK, ROS1, NTRK1, NTRK2, NTRK3, BRAF and MAP3K8, or some mutations, such as HRAS and MAP3K8. These chromosomal abnormalities act as drivers, initiating the oncogenetic process and conferring basic bio-morphological features. Most Spitz tumors show no additional genomic alterations or few ones; others harbor a variable number of mutations, capable of conferring characteristics related to clinical behavior, including CDKN2A deletion and TERT-p mutation. Since the accumulation of mutations is gradual and progressive, tumors appear to form a bio-morphologic spectrum, in which they show a progressive increase of clinical risk and histological atypia. In this context, a binary classification Spitz nevus-melanoma appears as no longer adequate, not corresponding to the real genomic substrate of lesions. A ternary classification Spitz nevus-Spitz melanocytoma-Spitz melanoma is more adherent to the real neoplastic pathway, but some cases with intermediate ambiguous features remain difficult to diagnose. A prognostic stratification of Spitz tumors, based on the morphologic and genomic characteristics, as a complement to the diagnosis, may contribute to better treatment plans for patients. Full article
(This article belongs to the Special Issue Melanoma: Pathology and Translational Research)
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