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Cells
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Skin Cancer: From Cellular and Molecular Mechanisms to Therapeutic Opportunities
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Skin Cancer: From Cellular and Molecular Mechanisms to Therapeutic Opportunities

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (15 August 2023) | Viewed by 9704

Special Issue Editors

Dr. Dinesh Pradhan

E-Mail Website
Guest Editor
Department of Pathology & Microbiology, University of Nebraska Medical Center, 983135 Nebraska Medical Center, Omaha, NE 68198-3135, USA
Interests: melanoma; cancer genetics and epigenetics; molecular biology; biomarkers; vulvar cancer; cutaneous lymphoma
Dr. Phyu P. Aung

E-Mail Website1 Website2
Guest Editor
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Interests: genomics; epigenetic; bioinformatics; histology; immunohistochemistry and functional assays of melanoma and Merkel cell carcinoma; biomarkers; cutaneous manifestation of drug toxicity; histologic and molecular findings related to treatment response

Special Issue Information

Dear Colleagues,

Skin cancer is the most common cancer in the United States and worldwide. The overall incidence of skin cancer is increasing. Basal cell and squamous cell carcinomas, the two most common forms of skin cancer, are highly treatable if detected early. However, the 5-year relative survival of melanoma and Merkel cell carcinoma with distant metastasis is as low as 32% and 21%, respectively. Sebaceous carcinoma are rare aggressive tumors with poor prognosis and association with Muir–Torre syndrome.

Skin cancer has the highest tumor mutational burden and highest objective response to immunotherapy (anti-PD-1 or anti-PD-L1 therapy). Numerous targeted therapies targeting known molecular alterations in melanoma have revolutionized its therapy. Better understanding of immunological abnormalities, molecular pathways, biomarkers, and epigenetics of melanoma have brought forth a paradigm shift in the management and survival of these patients.

The murine model of melanoma has better revealed the tumor immune microenvironment, elucidated the mechanism of PD-L1 depletion-induced cancer cell senescence via strong induction of stimulator of interferon gene (STING) expression, and demonstrated the potential of numerous immunomodulatory drugs. LS-007, an inhibitor of cyclin-dependent kinase 9 (CDK9), has inhibitory effects on B16F10 melanoma cells in vivo and in vitro via inducing apoptosis, and cell cycle arrest.

Dr. Dinesh Pradhan
Dr. Phyu P. Aung
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. Cells 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 2700 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

  • skin cancer
  • melanoma
  • Merkel cell carcinoma
  • skin lymphoma
  • squamous cell carcinoma
  • mycosis fungoides
  • adnexal tumors
  • sebaceous carcinoma
  • cutaneous soft tissue tumors
  • pleomorphic dermal sarcoma

Published Papers (6 papers)

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Research

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17 pages, 6899 KiB  
Article
Ectopically Expressed Meiosis-Specific Cancer Testis Antigen HORMAD1 Promotes Genomic Instability in Squamous Cell Carcinomas
by Jennifer Gantchev, Julia Messina-Pacheco, Amelia Martínez Villarreal, Brandon Ramchatesingh, Philippe Lefrançois, Pingxing Xie, Laetitia Amar, Hong Hao Xu, Keerthenan Raveendra, Daniel Sikorski, Daniel Josue Guerra Ordaz, Raman Preet Kaur Gill, Marine Lambert and Ivan V. Litvinov
Cells 2023, 12(12), 1627; https://doi.org/10.3390/cells12121627 - 14 Jun 2023
Cited by 1 | Viewed by 1344
Abstract
Genomic instability is a prominent hallmark of cancer, however the mechanisms that drive and sustain this process remain elusive. Research demonstrates that numerous cancers with increased levels of genomic instability ectopically express meiosis-specific genes and undergo meiomitosis, the clash of mitotic and meiotic [...] Read more.
Genomic instability is a prominent hallmark of cancer, however the mechanisms that drive and sustain this process remain elusive. Research demonstrates that numerous cancers with increased levels of genomic instability ectopically express meiosis-specific genes and undergo meiomitosis, the clash of mitotic and meiotic processes. These meiotic genes may represent novel therapeutic targets for the treatment of cancer. We studied the relationship between the expression of the meiosis protein HORMAD1 and genomic instability in squamous cell carcinomas (SCCs). First, we assessed markers of DNA damage and genomic instability following knockdown and overexpression of HORMAD1 in different cell lines representing SCCs and epithelial cancers. shRNA-mediated depletion of HORMAD1 expression resulted in increased genomic instability, DNA damage, increased sensitivity to etoposide, and decreased expression of DNA damage response/repair genes. Conversely, overexpression of HORMAD1 exhibited protective effects leading to decreased DNA damage, enhanced survival and decreased sensitivity to etoposide. Furthermore, we identified a meiotic molecular pathway that regulates HORMAD1 expression by targeting the upstream meiosis transcription factor STRA8. Our results highlight a specific relationship between HORMAD1 and genomic instability in SCCs, suggesting that selectively inhibiting HORMAD1, possibly, through STRA8 signaling, may provide a new paradigm of treatment options for HORMAD1-expressing SCCs. Full article
(This article belongs to the Special Issue Skin Cancer: From Cellular and Molecular Mechanisms to Therapeutic Opportunities)
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10 pages, 1746 KiB  
Communication
Is Cutaneous T-Cell Lymphoma Caused by Ultraviolet Radiation? A Comparison of UV Mutational Signatures in Malignant Melanoma and Mycosis Fungoides
by Robert Gniadecki, Sandra O’Keefe, Dylan Hennessey and Aishwarya Iyer
Cells 2023, 12(12), 1616; https://doi.org/10.3390/cells12121616 - 13 Jun 2023
Cited by 1 | Viewed by 1263
Abstract
Ultraviolet (UV) radiation is a strong environmental carcinogen responsible for the pathogenesis of most skin cancers, including malignant melanoma (MM) and non-melanoma (keratinocyte) skin cancers. The carcinogenic role of UV was firmly established based on epidemiological evidence and molecular findings of the characteristic [...] Read more.
Ultraviolet (UV) radiation is a strong environmental carcinogen responsible for the pathogenesis of most skin cancers, including malignant melanoma (MM) and non-melanoma (keratinocyte) skin cancers. The carcinogenic role of UV was firmly established based on epidemiological evidence and molecular findings of the characteristic mutation signatures which occur during the excision repair of cyclobutane pyrimidine dimers and 6,4-photoproducts. The role of UV in the pathogenesis of mycosis fungoides (MF), the most common type of primary cutaneous T-cell lymphoma, remains controversial. Here, we performed whole-exome sequencing of 61 samples of MF cells microdissected from cutaneous lesions, and compared their mutational signatures to 340 MMs. The vast majority of MM mutations had a typical UV mutational signature (SBS 7, SBS 38, or DSB 1), underscoring the key role of ultraviolet as a mutagen. In contrast, the SBS 7 signature in MF comprised < 5% of all mutations. SBS 7 was higher in the intraepidermal MF cells (when compared to the dermal cells) and in the cells from tumors as compared to that in early-stage plaques. In conclusion, our data do not support the pathogenic role of UV in the pathogenesis of MF and suggest that the UV mutations are the result of the cumulative environmental ultraviolet exposure of cutaneous lesions rather than an early mutagenic event. Full article
(This article belongs to the Special Issue Skin Cancer: From Cellular and Molecular Mechanisms to Therapeutic Opportunities)
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17 pages, 4006 KiB  
Article
Extracellular Vesicle-Packaged miR-195-5p Sensitizes Melanoma to Targeted Therapy with Kinase Inhibitors
by Nathalia L. Santos, Silvina O. Bustos, Patricia P. Reis, Roger Chammas and Luciana N. S. Andrade
Cells 2023, 12(9), 1317; https://doi.org/10.3390/cells12091317 - 05 May 2023
Cited by 4 | Viewed by 1543
Abstract
Management of advanced melanoma remains challenging, with most BRAF (B-Raf proto-oncogene, serine/threonine kinase)-mutated metastatic patients relapsing within a few months upon MAPK inhibitors treatment. Modulation of tumor-derived extracellular vesicle (EVs) cargo with enrichment of antitumoral molecules is a promising strategy to impair tumor [...] Read more.
Management of advanced melanoma remains challenging, with most BRAF (B-Raf proto-oncogene, serine/threonine kinase)-mutated metastatic patients relapsing within a few months upon MAPK inhibitors treatment. Modulation of tumor-derived extracellular vesicle (EVs) cargo with enrichment of antitumoral molecules is a promising strategy to impair tumor progression and increase treatment response. Herein, we report that restored expression of miR-195-5p, down-regulated in melanoma favoring drug resistance, increases the release of EVs enriched in the tumor suppressor miRNAs, miR-195-5p, miR-152-3p, and miR-202-3p. Incorporating these EVs by bystander tumor cells resulted in decreased proliferation and viability, accompanied by a reduction in CCND1 and YAP1 mRNA levels. Upon treatment with MAPK inhibitors, miR-195 EVs significantly decreased BCL2-L1 protein levels and increased cell death ratio and treatment efficacy. Additionally, EVs exogenously loaded with miR-195-5p by electroporation reduced tumor volume in vivo and impaired engraftment and growth of xenografts implanted with melanoma cells exposed to MAPK inhibitors. Our study shows that miR-195-5p antitumoral activity can be spread to bystander cells through EVs, improving melanoma response to targeted therapy and revealing a promising EV-based strategy to increase clinical response in patients harboring BRAF mutations. Full article
(This article belongs to the Special Issue Skin Cancer: From Cellular and Molecular Mechanisms to Therapeutic Opportunities)
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27 pages, 5989 KiB  
Article
The Activation of PPARγ by (2Z,4E,6E)-2-methoxyocta-2,4,6-trienoic Acid Counteracts the Epithelial–Mesenchymal Transition Process in Skin Carcinogenesis
by Enrica Flori, Sarah Mosca, Giorgia Cardinali, Stefania Briganti, Monica Ottaviani, Daniela Kovacs, Isabella Manni, Mauro Truglio, Arianna Mastrofrancesco, Marco Zaccarini, Carlo Cota, Giulia Piaggio and Mauro Picardo
Cells 2023, 12(7), 1007; https://doi.org/10.3390/cells12071007 - 24 Mar 2023
Viewed by 1496
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the most common UV-induced keratinocyte-derived cancer, and its progression is characterized by the epithelial–mesenchymal transition (EMT) process. We previously demonstrated that PPARγ activation by 2,4,6-octatrienoic acid (Octa) prevents cutaneous UV damage. We investigated the possible role of [...] Read more.
Cutaneous squamous cell carcinoma (cSCC) is the most common UV-induced keratinocyte-derived cancer, and its progression is characterized by the epithelial–mesenchymal transition (EMT) process. We previously demonstrated that PPARγ activation by 2,4,6-octatrienoic acid (Octa) prevents cutaneous UV damage. We investigated the possible role of the PPARγ activators Octa and the new compound (2Z,4E,6E)-2-methoxyocta-2,4,6-trienoic acid (A02) in targeting keratinocyte-derived skin cancer. Like Octa, A02 exerted a protective effect against UVB-induced oxidative stress and DNA damage in NHKs. In the squamous cell carcinoma A431 cells, A02 inhibited cell proliferation and increased differentiation markers’ expression. Moreover, Octa and even more A02 counteracted the TGF-β1-dependent increase in mesenchymal markers, intracellular ROS, the activation of EMT-related signal transduction pathways, and cells’ migratory capacity. Both compounds, especially A02, counterbalanced the TGF-β1-induced cell membrane lipid remodeling and the release of bioactive lipids involved in EMT. In vivo experiments on a murine model useful to study cell proliferation in adult animals showed the reduction of areas characterized by active cell proliferation in response to A02 topical treatment. In conclusion, targeting PPARγ may be useful for the prevention and treatment of keratinocyte-derived skin cancer. Full article
(This article belongs to the Special Issue Skin Cancer: From Cellular and Molecular Mechanisms to Therapeutic Opportunities)
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Review

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18 pages, 637 KiB  
Review
Immunity against Non-Melanoma Skin Cancer and the Effect of Immunosuppressive Medication on Non-Melanoma Skin Cancer Risk in Solid Organ Transplant Recipients
by Dixie Bakker, Walbert J. Bakker, Marcel W. Bekkenk and Rosalie M. Luiten
Cells 2023, 12(20), 2441; https://doi.org/10.3390/cells12202441 - 11 Oct 2023
Cited by 1 | Viewed by 1230
Abstract
Non-melanoma skin cancers (NMSCs) occur frequently in the Caucasian population and are considered a burden for health care. Risk factors include ultraviolet (UV) radiation, ethnicity and immunosuppression. The incidence of NMSC is significantly higher in solid organ transplant recipients (SOTRs) than in immunocompetent [...] Read more.
Non-melanoma skin cancers (NMSCs) occur frequently in the Caucasian population and are considered a burden for health care. Risk factors include ultraviolet (UV) radiation, ethnicity and immunosuppression. The incidence of NMSC is significantly higher in solid organ transplant recipients (SOTRs) than in immunocompetent individuals, due to immunosuppressive medication use by SOTRs. While the immunosuppressive agents, calcineurin inhibitors and purine analogues increase the incidence of NMSC in transplant recipients, mTOR inhibitors do not. This is most likely due to the different immunological pathways that are inhibited by each class of drug. This review will focus on what is currently known about the immune response against cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC), two of the main types of NMSC. Furthermore, we will describe the different classes of immunosuppressants given to SOTRs, which part of the immune system they target and how they can contribute to NMSC development. The risk of developing NMSC in SOTRs is the result of a combination of inhibiting immunological pathways involved in immunosurveillance against NMSC and the direct (pro/anti) tumor effects of immunosuppressants. Full article
(This article belongs to the Special Issue Skin Cancer: From Cellular and Molecular Mechanisms to Therapeutic Opportunities)
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14 pages, 1015 KiB  
Review
Riboflavin and Its Derivates as Potential Photosensitizers in the Photodynamic Treatment of Skin Cancers
by Małgorzata Insińska-Rak, Marek Sikorski and Agnieszka Wolnicka-Glubisz
Cells 2023, 12(18), 2304; https://doi.org/10.3390/cells12182304 - 19 Sep 2023
Cited by 1 | Viewed by 1662
Abstract
Riboflavin, a water-soluble vitamin B2, possesses unique biological and physicochemical properties. Its photosensitizing properties make it suitable for various biological applications, such as pathogen inactivation and photodynamic therapy. However, the effectiveness of riboflavin as a photosensitizer is hindered by its degradation upon exposure [...] Read more.
Riboflavin, a water-soluble vitamin B2, possesses unique biological and physicochemical properties. Its photosensitizing properties make it suitable for various biological applications, such as pathogen inactivation and photodynamic therapy. However, the effectiveness of riboflavin as a photosensitizer is hindered by its degradation upon exposure to light. The review aims to highlight the significance of riboflavin and its derivatives as potential photosensitizers for use in photodynamic therapy. Additionally, a concise overview of photodynamic therapy and utilization of blue light in dermatology is provided, as well as the photochemistry and photobiophysics of riboflavin and its derivatives. Particular emphasis is given to the latest findings on the use of acetylated 3-methyltetraacetyl-riboflavin derivative (3MeTARF) in photodynamic therapy. Full article
(This article belongs to the Special Issue Skin Cancer: From Cellular and Molecular Mechanisms to Therapeutic Opportunities)
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