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Novel Biomarkers and Therapeutic Targets for Melanoma
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Novel Biomarkers and Therapeutic Targets for Melanoma

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 16295

Special Issue Editors

Dr. Valentina Audrito

E-Mail Website
Guest Editor
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy
Interests: malignant melanoma; metabolic reprogramming; NAD-metabolizing enzymes; biomarker; microenvironment; therapy resistance; translational oncology
Special Issues, Collections and Topics in MDPI journals
Dr. Alice Indini

E-Mail Website
Guest Editor
Medical Oncology Unit, Ospedale di Circolo e Fondazione Macchi, ASST dei Settelaghi, Varese, Italy
Interests: melanoma; skin cancer; immunotherapy; targeted therapy; BRAF; MEK; resistance mechanisms

Special Issue Information

Dear Colleagues,

Malignant melanoma represents the most fatal skin cancer due to its aggressive biological behavior and high metastatic potential. Treatment strategies for advanced disease have dramatically changed over the last years, due to the introduction of BRAF/MEK inhibitors and immunotherapy. However, many patients either display primary (i.e., innate), or develop secondary (i.e., acquired) resistance to systemic treatments. Resistance is due to many complex and multiple mechanisms driven by a set of rewiring processes, which involve cancer metabolism, epigenetics, gene expression and interactions in the tumor microenvironment. Prognostic and predictive biomarkers are still needed to guide patients’ selection and treatment decisions. Indeed, there are no recognized clinical or biological characteristics that identify which patients will benefit more from available treatments, but several biomarkers have been studied with promising preliminary results.

In this Special Issue, we welcome research articles and reviews analyzing new insights into the molecular and cellular mechanisms underlying the progression of melanoma and the response to therapy, focusing on prognostic factors, biomarkers for risk stratification, treatment response and prognosis, and novel therapeutic strategies in the field of melanoma.

Dr. Valentina Audrito
Dr. Alice Indini
Guest Editors

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Keywords

  • melanoma
  • biomarkers
  • therapeutic targets
  • targeted therapy
  • immunotherapy
  • resistance
  • genetics
  • phenotype plasticity

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Published Papers (5 papers)

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Research

Jump to: Review

17 pages, 3960 KiB  
Article
The Prognostic Relevance of PMCA4 Expression in Melanoma: Gender Specificity and Implications for Immune Checkpoint Inhibition
by Luca Hegedüs, Elisabeth Livingstone, Ágnes Bánkfalvi, Jan Viehof, Ágnes Enyedi, Ágnes Bilecz, Balázs Győrffy, Marcell Baranyi, Anna-Mária Tőkés, Jeovanis Gil, György Marko-Varga, Klaus G. Griewank, Lisa Zimmer, Renáta Váraljai, Antje Sucker, Anne Zaremba, Dirk Schadendorf, Clemens Aigner and Balázs Hegedüs
Int. J. Mol. Sci. 2022, 23(6), 3324; https://doi.org/10.3390/ijms23063324 - 19 Mar 2022
Cited by 5 | Viewed by 2467
Abstract
PMCA4 is a critical regulator of Ca2+ homeostasis in mammalian cells. While its biological and prognostic relevance in several cancer types has already been demonstrated, only preclinical investigations suggested a metastasis suppressor function in melanoma. Therefore, we studied the expression pattern of [...] Read more.
PMCA4 is a critical regulator of Ca2+ homeostasis in mammalian cells. While its biological and prognostic relevance in several cancer types has already been demonstrated, only preclinical investigations suggested a metastasis suppressor function in melanoma. Therefore, we studied the expression pattern of PMCA4 in human skin, nevus, as well as in primary and metastatic melanoma using immunohistochemistry. Furthermore, we analyzed the prognostic power of PMCA4 mRNA levels in cutaneous melanoma both at the non-metastatic stage as well as after PD-1 blockade in advanced disease. PMCA4 localizes to the plasma membrane in a differentiation dependent manner in human skin and mucosa, while nevus cells showed no plasma membrane staining. In contrast, primary cutaneous, choroidal and conjunctival melanoma cells showed specific plasma membrane localization of PMCA4 with a wide range of intensities. Analyzing the TCGA cohort, PMCA4 mRNA levels showed a gender specific prognostic impact in stage I–III melanoma. Female patients with high transcript levels had a significantly longer progression-free survival. Melanoma cell specific PMCA4 protein expression is associated with anaplasticity in melanoma lung metastasis but had no impact on survival after lung metastasectomy. Importantly, high PMCA4 transcript levels derived from RNA-seq of cutaneous melanoma are associated with significantly longer overall survival after PD-1 blockade. In summary, we demonstrated that human melanoma cells express PMCA4 and PMCA4 transcript levels carry prognostic information in a gender specific manner. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutic Targets for Melanoma)
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19 pages, 4451 KiB  
Article
Salviolone from Salvia miltiorrhiza Roots Impairs Cell Cycle Progression, Colony Formation, and Metalloproteinase-2 Activity in A375 Melanoma Cells: Involvement of P21(Cip1/Waf1) Expression and STAT3 Phosphorylation
by Valentina Zanrè, Rachele Campagnari, Antonietta Cerulli, Milena Masullo, Alessia Cardile, Sonia Piacente and Marta Menegazzi
Int. J. Mol. Sci. 2022, 23(3), 1121; https://doi.org/10.3390/ijms23031121 - 20 Jan 2022
Cited by 8 | Viewed by 2703
Abstract
Melanoma is a highly malignant solid tumor characterized by an elevated growth and propagation rate. Since, often, melanoma treatment cannot prevent recurrences and the appearance of metastasis, new anti-melanoma agents need to be discovered. Salvia miltiorrhiza roots are a source of diterpenoid derivatives, [...] Read more.
Melanoma is a highly malignant solid tumor characterized by an elevated growth and propagation rate. Since, often, melanoma treatment cannot prevent recurrences and the appearance of metastasis, new anti-melanoma agents need to be discovered. Salvia miltiorrhiza roots are a source of diterpenoid derivatives, natural compounds with several biological activities, including antiproliferative and anticancer effects. Seven diterpenoid derivatives were purified from S. miltiorrhiza roots and identified by NMR and MS analysis. Tanshinone IIA and cryptotanshinone were detected as the main components of S. miltiorrhiza root ethanol extract. Although their antitumor activity is already known, they have been confirmed to induce a reduction in A375 and MeWo melanoma cell growth. Likewise, salviolone has been shown to impair the viability of melanoma cells without affecting the growth of normal melanocytes. The underlying anticancer activity of salviolone has been investigated and compared to that of cryptotanshinone in A375 cells, showing an increased P21 protein expression in a P53-dependent manner. In that way, salviolone, even more than cryptotanshinone, displays a multitarget effect on cell-cycle-related proteins. Besides, it modulates the phosphorylation level of the signal transducer and activator of transcription (STAT)3. Unexpectedly, salviolone and cryptotanshinone induce sustained activation of the extracellular signal-regulated kinases (ERK)1/2 and the protein kinase B (Akt). However, the blockage of ERK1/2 or Akt activities suggests that kinase activation does not hinder their ability to inhibit A375 cell growth. Finally, salviolone and cryptotanshinone inhibit to a comparable extent some crucial malignancy features of A375 melanoma cells, such as colony formation in soft agar and metalloproteinase-2 activity. In conclusion, it has been shown for the first time that salviolone, harboring a different molecular structure than tanshinone IIA and cryptotanshinone, exhibits a pleiotropic effect against melanoma by hampering cell cycle progression, STAT3 signaling, and malignant phenotype of A375 melanoma cells. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutic Targets for Melanoma)
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Review

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10 pages, 271 KiB  
Review
Novel Biomarkers and Therapeutic Targets for Melanoma
by Noa Sabag, Alexander Yakobson, Meir Retchkiman and Eldad Silberstein
Int. J. Mol. Sci. 2022, 23(19), 11656; https://doi.org/10.3390/ijms231911656 - 1 Oct 2022
Cited by 8 | Viewed by 2089
Abstract
Malignant melanoma is one of the most common cancers in the world. In the disease’s early stages, treatment involves surgery, in advanced stages however, treatment options were once scarce. There has been a paradigm shift in advanced melanoma treatment with the introduction of [...] Read more.
Malignant melanoma is one of the most common cancers in the world. In the disease’s early stages, treatment involves surgery, in advanced stages however, treatment options were once scarce. There has been a paradigm shift in advanced melanoma treatment with the introduction of immunotherapy and targeted therapies. Understanding the molecular pathways and their pathologic counterparts helped identifying specific biomarkers that lead to the development of specific targeted therapies. In this review we briefly present some of these markers and their relevance to melanoma treatment. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutic Targets for Melanoma)
33 pages, 2339 KiB  
Review
NAD/NAMPT and mTOR Pathways in Melanoma: Drivers of Drug Resistance and Prospective Therapeutic Targets
by Alice Indini, Irene Fiorilla, Luca Ponzone, Enzo Calautti and Valentina Audrito
Int. J. Mol. Sci. 2022, 23(17), 9985; https://doi.org/10.3390/ijms23179985 - 1 Sep 2022
Cited by 14 | Viewed by 4780
Abstract
Malignant melanoma represents the most fatal skin cancer due to its aggressive behavior and high metastatic potential. The introduction of BRAF/MEK inhibitors and immune-checkpoint inhibitors (ICIs) in the clinic has dramatically improved patient survival over the last decade. However, many patients either display [...] Read more.
Malignant melanoma represents the most fatal skin cancer due to its aggressive behavior and high metastatic potential. The introduction of BRAF/MEK inhibitors and immune-checkpoint inhibitors (ICIs) in the clinic has dramatically improved patient survival over the last decade. However, many patients either display primary (i.e., innate) or develop secondary (i.e., acquired) resistance to systemic treatments. Therapeutic resistance relies on the rewiring of multiple processes, including cancer metabolism, epigenetics, gene expression, and interactions with the tumor microenvironment that are only partially understood. Therefore, reliable biomarkers of resistance or response, capable of facilitating the choice of the best treatment option for each patient, are currently missing. Recently, activation of nicotinamide adenine dinucleotide (NAD) metabolism and, in particular, of its rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT) have been identified as key drivers of targeted therapy resistance and melanoma progression. Another major player in this context is the mammalian target of rapamycin (mTOR) pathway, which plays key roles in the regulation of melanoma cell anabolic functions and energy metabolism at the switch between sensitivity and resistance to targeted therapy. In this review, we summarize known resistance mechanisms to ICIs and targeted therapy, focusing on metabolic adaptation as one main mechanism of drug resistance. In particular, we highlight the roles of NAD/NAMPT and mTOR signaling axes in this context and overview data in support of their inhibition as a promising strategy to overcome treatment resistance. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutic Targets for Melanoma)
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18 pages, 1257 KiB  
Review
Role of HMGB1 in Cutaneous Melanoma: State of the Art
by Federica Li Pomi, Francesco Borgia, Paolo Custurone, Mario Vaccaro, Giovanni Pioggia and Sebastiano Gangemi
Int. J. Mol. Sci. 2022, 23(16), 9327; https://doi.org/10.3390/ijms23169327 - 18 Aug 2022
Cited by 21 | Viewed by 3187
Abstract
High-mobility Group Box 1 (HMGB1) is a nuclear protein that plays a key role in acute and chronic inflammation. It has already been studied in several diseases, among them melanoma. Indeed, HMGB1 is closely associated with cell survival and proliferation and may be [...] Read more.
High-mobility Group Box 1 (HMGB1) is a nuclear protein that plays a key role in acute and chronic inflammation. It has already been studied in several diseases, among them melanoma. Indeed, HMGB1 is closely associated with cell survival and proliferation and may be directly involved in tumor cell metastasis development thanks to its ability to promote cell migration. This research aims to assess the role of this molecule in the pathogenesis of human melanoma and its potential therapeutic role. The research has been conducted on the PubMed database, and the resulting articles are sorted by year of publication, showing an increasing interest in the last five years. The results showed that HMGB1 plays a crucial role in the pathogenesis of skin cancer, prognosis, and therapeutical response to therapy. Traditional therapies target this molecule indirectly, but future perspectives could include the development of new target therapy against HMGB1, thus adding a new approach to the therapy, which has often shown primary and secondary resistance. This could add a new therapy arm which has to be prolonged and specific for each patient. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutic Targets for Melanoma)
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