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Precision Oncology in Melanoma Progression
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Precision Oncology in Melanoma Progression

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 43423

Special Issue Editors

Dr. Simona D’Aguanno

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Guest Editor
Preclinical Models and New Therapeutic Agents Unit, Translational Research Functional Departmental Area, Research, Advanced Diagnostics and Technological Innovation Department, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
Interests: cancer research; melanoma; personalized precision medicine; pathway-targeted drugs; bcl-2 family protein; cancer biomarkers; microRNA; proteomics
Special Issues, Collections and Topics in MDPI journals
Dr. Sara Cingarlini

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Guest Editor
Medical Oncology, University and Hospital Trust of Verona, Verona, Department of Surgery and Oncology, Section of Oncology, ENETS Center of Excellence, University Hospital of Verona, Piazzale Ludovico Antonio Scuro 1, 37100 Verona, Italy

Special Issue Information

Dear Colleagues,

Melanoma represents the most malignant type of skin cancer, with increasing incidence worldwide. The alteration of the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signal transduction pathways are key mechanisms involved in the development of melanoma. Moreover, melanoma has long been at the cutting edge of immuno-oncology research, and immunotherapies such as cytokines, adoptive cell transfer, and T-cell modulators represented the first, pioneering approaches. In this scenario, checkpoint inhibitor therapy constitutes the most current and effective treatment strategy that targets immune checkpoints to re-activate silenced T cell cytotoxicity.

Despite the remarkable progress in melanoma diagnosis, research, and new therapeutic approaches, therapy of the advanced stage of this tumor is still rather limited. Common resistance mechanisms bypass the dependence of tumor cells on initial driver mutations during targeted therapy. Similarly, several factors contribute to this immune evasion. Additionally, the tumor microenvironment can facilitate tumor progression with cytokines, chemokines, and inhibitory factors or can recruit immunosuppressive immune cells, including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages.

This Special Issue will be dedicated to summarizing the state-of-the-art in precision diagnosis and treatment of melanoma and will focus on genetic diagnosis, molecular mechanisms of resistance to targeted and immune-therapies, strategies to overcome resistance, and monitoring of disease progression and relapse under therapy (e.g., by liquid biopsy), to provide updated information on the current status of molecular, pharmaceutical, and translational scientific discoveries.

Authors are encouraged to submit original research manuscripts but can also provide suggestions for review articles.

Potential topics will include but are not limited to:

  • Novel biomarkers for the early diagnosis and progression of melanoma;
  • Molecular, genetic, and cellular alterations associated with melanoma;
  • Genomic, transcriptomic, and tumor-infiltrating immune cell profiles in predicting immune checkpoint blockade response;
  • Potential synergic effects of small molecules and immunotherapy in facing melanoma progression;
  • Novel therapeutic strategies to overcome drug resistance melanoma;
  • Application of -omics technologies in precision oncology in melanoma progression.

Dr. Simona D'Aguanno
Dr. Sara Cingarlini
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • Precision oncology
  • Biomarker
  • Melanoma
  • Target therapy
  • Immunetherapy
  • Therapy resistance
  • Omics
  • Molecular genetics
  • Oncogene signaling pathways
  • Tumor microenvironment

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

4 pages, 173 KiB  
Editorial
Special Issue “Precision Oncology in Melanoma Progression”
by Simona D’Aguanno
Int. J. Mol. Sci. 2021, 22(14), 7723; https://doi.org/10.3390/ijms22147723 - 20 Jul 2021
Viewed by 1922
Abstract
Melanoma represents the most malignant type of skin cancer, with increasing incidence worldwide [...] Full article
(This article belongs to the Special Issue Precision Oncology in Melanoma Progression)

Research

Jump to: Editorial, Review

14 pages, 3047 KiB  
Article
Profiling Cancer-Associated Fibroblasts in Melanoma
by Federica Papaccio, Daniela Kovacs, Barbara Bellei, Silvia Caputo, Emilia Migliano, Carlo Cota and Mauro Picardo
Int. J. Mol. Sci. 2021, 22(14), 7255; https://doi.org/10.3390/ijms22147255 - 6 Jul 2021
Cited by 37 | Viewed by 3801
Abstract
Solid tumors are complex systems characterized by dynamic interactions between neoplastic cells, non-tumoral cells, and extracellular components. Among all the stromal cells that populate tumor microenvironment, fibroblasts are the most abundant elements and are critically involved in disease progression. Cancer-associated fibroblasts (CAFs) have [...] Read more.
Solid tumors are complex systems characterized by dynamic interactions between neoplastic cells, non-tumoral cells, and extracellular components. Among all the stromal cells that populate tumor microenvironment, fibroblasts are the most abundant elements and are critically involved in disease progression. Cancer-associated fibroblasts (CAFs) have pleiotropic functions in tumor growth and extracellular matrix remodeling implicated in local invasion and distant metastasis. CAFs additionally participate in the inflammatory response of the tumor site by releasing a variety of chemokines and cytokines. It is becoming clear that understanding the dynamic, mutual melanoma–fibroblast relationship would enable treatment options to be amplified. To better characterize melanoma-associated fibroblasts, here we analyzed low-passage primary CAFs derived from advanced-stage primary skin melanomas, focusing on the immuno-phenotype. Furthermore, we assessed the expression of several CAF markers and the production of growth factors. To deepen the study of CAF–melanoma cell crosstalk, we employed CAF-derived supernatants and trans-well co-culture systems to evaluate the influences of CAFs on (i) the motogenic ability of melanoma cells, (ii) the chemotherapy-induced cytotoxicity, and (iii) the release of mediators active in modulating tumor growth and spread. Full article
(This article belongs to the Special Issue Precision Oncology in Melanoma Progression)
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17 pages, 2319 KiB  
Article
Pigmentation Levels Affect Melanoma Responses to Coriolus versicolor Extract and Play a Crucial Role in Melanoma-Mononuclear Cell Crosstalk
by Małgorzata Pawlikowska, Tomasz Jędrzejewski, Andrzej T. Slominski, Anna A. Brożyna and Sylwia Wrotek
Int. J. Mol. Sci. 2021, 22(11), 5735; https://doi.org/10.3390/ijms22115735 - 27 May 2021
Cited by 15 | Viewed by 3554
Abstract
Melanoma, the malignancy originating from pigment-producing melanocytes, is the most aggressive form of skin cancer and has a poor prognosis once the disease starts to metastasize. The process of melanin synthesis generates an immunosuppressive and mutagenic environment, and can increase melanoma cell resistance [...] Read more.
Melanoma, the malignancy originating from pigment-producing melanocytes, is the most aggressive form of skin cancer and has a poor prognosis once the disease starts to metastasize. The process of melanin synthesis generates an immunosuppressive and mutagenic environment, and can increase melanoma cell resistance to different treatment modalities, including chemo-, radio- or photodynamic therapy. Recently, we have shown that the presence of melanin pigment inhibits the melanoma cell response to bioactive components of Coriolus versicolor (CV) Chinese fungus. Herein, using the same human melanoma cell line in which the level of pigmentation can be controlled by the L-tyrosine concentration in culture medium, we tested the effect of suppression of melanogenesis on the melanoma cell response to CV extract and investigated the cell death pathway induced by fungus extract in sensitized melanoma cells. Our data showed that susceptibility to CV-induced melanoma cell death is significantly increased after cell depigmentation. To the best of our knowledge, we are the first to demonstrate that CV extract can induce RIPK1/RIPK3/MLKL-mediated necroptosis in depigmented melanoma cells. Moreover, using the co-culture system, we showed that inhibition of the tyrosinase activity in melanoma cells modulates cytokine expression in co-cultured mononuclear cells, indicating that depigmentation of melanoma cells may activate immune cells and thereby influence a host anticancer response. Full article
(This article belongs to the Special Issue Precision Oncology in Melanoma Progression)
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17 pages, 2530 KiB  
Article
Higher Mutation Burden in High Proliferation Compartments of Heterogeneous Melanoma Tumors
by Tomasz M. Grzywa, Agnieszka A. Koppolu, Wiktor Paskal, Klaudia Klicka, Małgorzata Rydzanicz, Jarosław Wejman, Rafał Płoski and Paweł K. Włodarski
Int. J. Mol. Sci. 2021, 22(8), 3886; https://doi.org/10.3390/ijms22083886 - 9 Apr 2021
Cited by 7 | Viewed by 2942
Abstract
Melanoma tumors are the most heterogeneous of all tumor types. Tumor heterogeneity results in difficulties in diagnosis and is a frequent cause of failure in treatment. Novel techniques enable accurate examination of the tumor cells, considering their heterogeneity. The study aimed to determine [...] Read more.
Melanoma tumors are the most heterogeneous of all tumor types. Tumor heterogeneity results in difficulties in diagnosis and is a frequent cause of failure in treatment. Novel techniques enable accurate examination of the tumor cells, considering their heterogeneity. The study aimed to determine the somatic variations among high and low proliferating compartments of melanoma tumors. In this study, 12 archival formalin-fixed paraffin-embedded samples of previously untreated primary cutaneous melanoma were stained with Ki-67 antibody. High and low proliferating compartments from four melanoma tumors were dissected using laser-capture microdissection. DNA was isolated and analyzed quantitatively and qualitatively. Libraries for amplicon-based next-generation sequencing (NGS) were prepared using NEBNext Direct Cancer HotSpot Panel. NGS detected 206 variants in 42 genes in melanoma samples. Most of them were located within exons (135, 66%) and were predominantly non-synonymous single nucleotide variants (99, 73.3%). The analysis showed significant differences in mutational profiles between high and low proliferation compartments of melanoma tumors. Moreover, a significantly higher percentage of variants were detected only in high proliferation compartments (39%) compared to low proliferation regions (16%, p < 0.05). Our results suggest a significant functional role of genetic heterogeneity in melanoma. Full article
(This article belongs to the Special Issue Precision Oncology in Melanoma Progression)
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14 pages, 3062 KiB  
Article
Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance
by Namkyoung Kim, Injae Shin, Jiwon Lee, Eunhye Jeon, Younghoon Kim, Seongshick Ryu, Eunhye Ju, Wonjeong Cho and Taebo Sim
Int. J. Mol. Sci. 2021, 22(7), 3783; https://doi.org/10.3390/ijms22073783 - 6 Apr 2021
Cited by 9 | Viewed by 3884
Abstract
Melanoma accounts for the majority of skin cancer deaths. About 50% of all melanomas are associated with BRAF mutations. BRAF mutations are classified into three classes with regard to dependency on RAF dimerization and RAS signaling. The most frequently occurring class I BRAF [...] Read more.
Melanoma accounts for the majority of skin cancer deaths. About 50% of all melanomas are associated with BRAF mutations. BRAF mutations are classified into three classes with regard to dependency on RAF dimerization and RAS signaling. The most frequently occurring class I BRAF V600 mutations are sensitive to vemurafenib whereas class II and class III mutants, non-V600 BRAF mutants are resistant to vemurafenib. Herein we report six pyrimido[4,5-d]pyrimidin-2-one derivatives possessing highly potent anti-proliferative activities on melanoma cells harboring BRAF class I/II/III mutants. Novel and most potent derivative, SIJ1777, possesses not only two-digit nanomolar potency but also 2 to 14-fold enhanced anti-proliferative activities compared with reference compound, GNF-7 against melanoma cells (SK-MEL-2, SK-MEL-28, A375, WM3670, WM3629). Moreover, SIJ1777 substantially inhibits the activation of MEK, ERK, and AKT and remarkably induces apoptosis and significantly blocks migration, invasion, and anchorage-independent growth of melanoma cells harboring BRAF class I/II/II mutations while both vemurafenib and PLX8394 have little to no effects on melanoma cells expressing BRAF class II/III mutations. Taken together, our six GNF-7 derivatives exhibit highly potent activities against melanoma cells harboring class I/II/III BRAF mutations compared with vemurafenib as well as PLX8394. Full article
(This article belongs to the Special Issue Precision Oncology in Melanoma Progression)
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Review

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16 pages, 3570 KiB  
Review
Prognostic and Predictive Biomarkers in Stage III Melanoma: Current Insights and Clinical Implications
by Luca Tonella, Valentina Pala, Renata Ponti, Marco Rubatto, Giuseppe Gallo, Luca Mastorino, Gianluca Avallone, Martina Merli, Andrea Agostini, Paolo Fava, Luca Bertero, Rebecca Senetta, Simona Osella-Abate, Simone Ribero, Maria Teresa Fierro and Pietro Quaglino
Int. J. Mol. Sci. 2021, 22(9), 4561; https://doi.org/10.3390/ijms22094561 - 27 Apr 2021
Cited by 26 | Viewed by 3975
Abstract
Melanoma is one of the most aggressive skin cancers. The 5-year survival rate of stage III melanoma patients ranges from 93% (IIIA) to 32% (IIID) with a high risk of recurrence after complete surgery. The introduction of target and immune therapies has dramatically [...] Read more.
Melanoma is one of the most aggressive skin cancers. The 5-year survival rate of stage III melanoma patients ranges from 93% (IIIA) to 32% (IIID) with a high risk of recurrence after complete surgery. The introduction of target and immune therapies has dramatically improved the overall survival, but the identification of patients with a high risk of relapse who will benefit from adjuvant therapy and the determination of the best treatment choice remain crucial. Currently, patient prognosis is based on clinico-pathological features, highlighting the urgent need of predictive and prognostic markers to improve patient management. In recent years, many groups have focused their attention on identifying molecular biomarkers with prognostic and predictive potential. In this review, we examined the main candidate biomarkers reported in the literature. Full article
(This article belongs to the Special Issue Precision Oncology in Melanoma Progression)
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18 pages, 516 KiB  
Review
Precision Medicine and Melanoma: Multi-Omics Approaches to Monitoring the Immunotherapy Response
by Fabio Valenti, Italia Falcone, Sara Ungania, Flora Desiderio, Patrizio Giacomini, Chiara Bazzichetto, Fabiana Conciatori, Enzo Gallo, Francesco Cognetti, Gennaro Ciliberto, Aldo Morrone and Antonino Guerrisi
Int. J. Mol. Sci. 2021, 22(8), 3837; https://doi.org/10.3390/ijms22083837 - 7 Apr 2021
Cited by 28 | Viewed by 5719
Abstract
The treatment and management of patients with metastatic melanoma have evolved considerably in the “era” of personalized medicine. Melanoma was one of the first solid tumors to benefit from immunotherapy; life expectancy for patients in advanced stage of disease has improved. However, many [...] Read more.
The treatment and management of patients with metastatic melanoma have evolved considerably in the “era” of personalized medicine. Melanoma was one of the first solid tumors to benefit from immunotherapy; life expectancy for patients in advanced stage of disease has improved. However, many progresses have yet to be made considering the (still) high number of patients who do not respond to therapies or who suffer adverse events. In this scenario, precision medicine appears fundamental to direct the most appropriate treatment to the single patient and to guide towards treatment decisions. The recent multi-omics analyses (genomics, transcriptomics, proteomics, metabolomics, radiomics, etc.) and the technological evolution of data interpretation have allowed to identify and understand several processes underlying the biology of cancer; therefore, improving the tumor clinical management. Specifically, these approaches have identified new pharmacological targets and potential biomarkers used to predict the response or adverse events to treatments. In this review, we will analyze and describe the most important omics approaches, by evaluating the methodological aspects and progress in melanoma precision medicine. Full article
(This article belongs to the Special Issue Precision Oncology in Melanoma Progression)
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23 pages, 780 KiB  
Review
BRAF Gene and Melanoma: Back to the Future
by Margaret Ottaviano, Emilio Francesco Giunta, Marianna Tortora, Marcello Curvietto, Laura Attademo, Davide Bosso, Cinzia Cardalesi, Mario Rosanova, Pietro De Placido, Erica Pietroluongo, Vittorio Riccio, Brigitta Mucci, Sara Parola, Maria Grazia Vitale, Giovannella Palmieri, Bruno Daniele, Ester Simeone and on behalf of SCITO YOUTH
Int. J. Mol. Sci. 2021, 22(7), 3474; https://doi.org/10.3390/ijms22073474 - 27 Mar 2021
Cited by 53 | Viewed by 7002
Abstract
As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected [...] Read more.
As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients. Full article
(This article belongs to the Special Issue Precision Oncology in Melanoma Progression)
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25 pages, 1407 KiB  
Review
Thinking Small: Small Molecules as Potential Synergistic Adjuncts to Checkpoint Inhibition in Melanoma
by Alexander C. Chacon, Alexa D. Melucci, Shuyang S. Qin and Peter A. Prieto
Int. J. Mol. Sci. 2021, 22(6), 3228; https://doi.org/10.3390/ijms22063228 - 22 Mar 2021
Cited by 6 | Viewed by 2980
Abstract
Metastatic melanoma remains the deadliest form of skin cancer. Immune checkpoint inhibition (ICI) immunotherapy has defined a new age in melanoma treatment, but responses remain inconsistent and some patients develop treatment resistance. The myriad of newly developed small molecular (SM) inhibitors of specific [...] Read more.
Metastatic melanoma remains the deadliest form of skin cancer. Immune checkpoint inhibition (ICI) immunotherapy has defined a new age in melanoma treatment, but responses remain inconsistent and some patients develop treatment resistance. The myriad of newly developed small molecular (SM) inhibitors of specific effector targets now affords a plethora of opportunities to increase therapeutic responses, even in resistant melanoma. In this review, we will discuss the multitude of SM classes currently under investigation, current and prospective clinical combinations of ICI and SM therapies, and their potential for synergism in melanoma eradication based on established mechanisms of immunotherapy resistance. Full article
(This article belongs to the Special Issue Precision Oncology in Melanoma Progression)
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21 pages, 1669 KiB  
Review
Stromal Cells Present in the Melanoma Niche Affect Tumor Invasiveness and Its Resistance to Therapy
by Justyna Mazurkiewicz, Aleksandra Simiczyjew, Ewelina Dratkiewicz, Marcin Ziętek, Rafał Matkowski and Dorota Nowak
Int. J. Mol. Sci. 2021, 22(2), 529; https://doi.org/10.3390/ijms22020529 - 7 Jan 2021
Cited by 27 | Viewed by 6364
Abstract
Malignant melanoma is a highly metastatic type of cancer, which arises frequently from transformed pigment cells and melanocytes as a result of long-term UV radiation exposure. In recent years, the incidence of newly diagnosed melanoma patients reached 5% of all cancer cases. Despite [...] Read more.
Malignant melanoma is a highly metastatic type of cancer, which arises frequently from transformed pigment cells and melanocytes as a result of long-term UV radiation exposure. In recent years, the incidence of newly diagnosed melanoma patients reached 5% of all cancer cases. Despite the development of novel targeted therapies directed against melanoma-specific markers, patients’ response to treatment is often weak or short-term due to a rapid acquisition of drug resistance. Among the factors affecting therapy effectiveness, elements of the tumor microenvironment play a major role. Melanoma niche encompasses adjacent cells, such as keratinocytes, cancer-associated fibroblasts (CAFs), adipocytes, and immune cells, as well as components of the extracellular matrix and tumor-specific physicochemical properties. In this review, we summarize the current knowledge concerning the influence of cancer-associated cells (keratinocytes, CAFs, adipocytes) on the process of melanomagenesis, tumor progression, invasiveness, and the emergence of drug resistance in melanoma. We also address how melanoma can alter the differentiation and activation status of cells present in the tumor microenvironment. Understanding these complex interactions between malignant and cancer-associated cells could improve the development of effective antitumor therapeutic strategies. Full article
(This article belongs to the Special Issue Precision Oncology in Melanoma Progression)
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