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15 pages, 10565 KiB

Open AccessArticle

A Proteomics Approach Identifies RREB1 as a Crucial Molecular Target of Imidazo–Pyrazole Treatment in SKMEL-28 Melanoma Cells

by Erika Iervasi, Gabriela Coronel Vargas, Tiziana Bachetti, Kateryna Tkachenko, Andrea Spallarossa, Chiara Brullo, Camillo Rosano, Sonia Carta, Paola Barboro, Aldo Profumo and Marco Ponassi

Int. J. Mol. Sci. 2024, 25(12), 6760; https://doi.org/10.3390/ijms25126760 - 20 Jun 2024

Viewed by 1169

Abstract

Cutaneous melanoma is the most dangerous and deadly form of human skin malignancy. Despite its rarity, it accounts for a staggering 80% of deaths attributed to cutaneous cancers overall. Moreover, its final stages often exhibit resistance to drug treatments, resulting in unfavorable outcomes. [...] Read more.

Cutaneous melanoma is the most dangerous and deadly form of human skin malignancy. Despite its rarity, it accounts for a staggering 80% of deaths attributed to cutaneous cancers overall. Moreover, its final stages often exhibit resistance to drug treatments, resulting in unfavorable outcomes. Hence, ensuring access to novel and improved chemotherapeutic agents is imperative for patients grappling with this severe ailment. Pyrazole and its fused systems derived thereof are heteroaromatic moieties widely employed in medicinal chemistry to develop effective drugs for various therapeutic areas, including inflammation, pain, oxidation, pathogens, depression, and fever. In a previous study, we described the biochemical properties of a newly synthesized group of imidazo–pyrazole compounds. In this paper, to improve our knowledge of the pharmacological properties of these molecules, we conduct a differential proteomic analysis on a human melanoma cell line treated with one of these imidazo–pyrazole derivatives. Our results detail the changes to the SKMEL-28 cell line proteome induced by 24, 48, and 72 h of 3e imidazo–pyrazole treatment. Notably, we highlight the down-regulation of the Ras-responsive element binding protein 1 (RREB1), a member of the zinc finger transcription factors family involved in the tumorigenesis of melanoma. RREB1 is a downstream element of the MAPK pathway, and its activation is mediated by ERK1/2 through phosphorylation. Full article

(This article belongs to the Special Issue Advances in Melanoma Immunotherapy and Molecular Mechanisms of Drug Resistance)

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31 pages, 6456 KiB

Open AccessArticle

Melanoma Cells Produce Large Vesicular-Bodies That Cause Rapid Disruption of Brain Endothelial Barrier-Integrity and Disassembly of Junctional Proteins

by Dayna Spurling, Akshata Anchan, James Hucklesby, Graeme Finlay, Catherine E. Angel and E. Scott Graham

Int. J. Mol. Sci. 2023, 24(7), 6082; https://doi.org/10.3390/ijms24076082 - 23 Mar 2023

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Abstract

It is known that many cells produce extracellular vesicles, and this includes a range of different cancer cell types. Here we demonstrate the profound effects of large vesicular-like bodies produced by melanoma cells on the barrier integrity of human brain endothelial cells. These [...] Read more.

It is known that many cells produce extracellular vesicles, and this includes a range of different cancer cell types. Here we demonstrate the profound effects of large vesicular-like bodies produced by melanoma cells on the barrier integrity of human brain endothelial cells. These vesicular-bodies have not been fully characterised but range in size from ~500 nm to >10 µm, are surrounded by membrane and are enzymatically active based on cell-tracker incorporation. Their size is consistent with previously reported large oncosomes and apoptotic bodies. We demonstrate that these melanoma-derived vesicular-bodies rapidly affect brain endothelial barrier integrity, measured using ECIS biosensor technology, where the disruption is evident within ~60 min. This disruption involves acquisition of the vesicles through transcellular uptake into the endothelial cells. We also observed extensive actin-rearrangement, actin removal from the paracellular boundary of the endothelial cells and envelopment of the vesicular-bodies by actin. This was concordant with widespread changes in CD144 localisation, which was consistent with the loss of junctional strength. High-resolution confocal imaging revealed proximity of the melanoma vesicular-bodies juxtaposed to the endothelial nucleus, often containing fragmented DNA themselves, raising speculation over this association and potential delivery of nuclear material into the brain endothelial cells. The disruption of the endothelial cells occurs in a manner that is faster and completely distinct to that of invasion by intact melanoma cells. Given the clinical observation of large vesicles in the circulation of melanoma patients by others, we hypothesize their involvement in weakening or priming the brain vasculature for melanoma invasion. Full article

(This article belongs to the Special Issue Advances in Melanoma Immunotherapy and Molecular Mechanisms of Drug Resistance)

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23 pages, 4050 KiB

Open AccessArticle

Enhanced Apoptosis and Loss of Cell Viability in Melanoma Cells by Combined Inhibition of ERK and Mcl-1 Is Related to Loss of Mitochondrial Membrane Potential, Caspase Activation and Upregulation of Proapoptotic Bcl-2 Proteins

by Zhe Peng, Bernhard Gillissen, Antje Richter, Tobias Sinnberg, Max S. Schlaak and Jürgen Eberle

Int. J. Mol. Sci. 2023, 24(5), 4961; https://doi.org/10.3390/ijms24054961 - 4 Mar 2023

Cited by 5 | Viewed by 2680

Abstract

Targeting of MAP kinase pathways by BRAF inhibitors has evolved as a key therapy for BRAF-mutated melanoma. However, it cannot be applied for BRAF-WT melanoma, and also, in BRAF-mutated melanoma, tumor relapse often follows after an initial phase of tumor regression. Inhibition of [...] Read more.

Targeting of MAP kinase pathways by BRAF inhibitors has evolved as a key therapy for BRAF-mutated melanoma. However, it cannot be applied for BRAF-WT melanoma, and also, in BRAF-mutated melanoma, tumor relapse often follows after an initial phase of tumor regression. Inhibition of MAP kinase pathways downstream at ERK1/2, or inhibitors of antiapoptotic Bcl-2 proteins, such as Mcl-1, may serve as alternative strategies. As shown here, the BRAF inhibitor vemurafenib and the ERK inhibitor SCH772984 showed only limited efficacy in melanoma cell lines, when applied alone. However, in combination with the Mcl-1 inhibitor S63845, the effects of vemurafenib were strongly enhanced in BRAF-mutated cell lines, and the effects of SCH772984 were enhanced in both BRAF-mutated and BRAF-WT cells. This resulted in up to 90% loss of cell viability and cell proliferation, as well as in induction of apoptosis in up to 60% of cells. The combination of SCH772984/S63845 resulted in caspase activation, processing of poly (ADP-ribose) polymerase (PARP), phosphorylation of histone H2AX, loss of mitochondrial membrane potential, and cytochrome c release. Proving the critical role of caspases, a pan-caspase inhibitor suppressed apoptosis induction, as well as loss of cell viability. As concerning Bcl-2 family proteins, SCH772984 enhanced expression of the proapoptotic Bim and Puma, as well as decreased phosphorylation of Bad. The combination finally resulted in downregulation of antiapoptotic Bcl-2 and enhanced expression of the proapoptotic Noxa. In conclusion, combined inhibition of ERK and Mcl-1 revealed an impressive efficacy both in BRAF-mutated and WT melanoma cells, and may thus represent a new strategy for overcoming drug resistance. Full article

(This article belongs to the Special Issue Advances in Melanoma Immunotherapy and Molecular Mechanisms of Drug Resistance)

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Review

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11 pages, 5680 KiB

Open AccessReview

Electrochemotherapy of Melanoma Cutaneous Metastases in Organ Transplant Recipients: A Systematic Review of Preclinical and Clinical Studies

by Sara Milicevic, Maja Cemazar, Andreja Klevisar Ivancic, Gorana Gasljevic, Masa Bosnjak, Gregor Sersa and Barbara Peric

Int. J. Mol. Sci. 2023, 24(9), 8335; https://doi.org/10.3390/ijms24098335 - 6 May 2023

Cited by 6 | Viewed by 2493

Abstract

Cutaneous melanoma is a highly aggressive form of skin cancer. The development of immune checkpoint inhibitors (ICIs) has revolutionized the management of advanced melanoma, led to durable responses, and improved overall survival. However, the success of ICIs in melanoma treatment is influenced by [...] Read more.

Cutaneous melanoma is a highly aggressive form of skin cancer. The development of immune checkpoint inhibitors (ICIs) has revolutionized the management of advanced melanoma, led to durable responses, and improved overall survival. However, the success of ICIs in melanoma treatment is influenced by the tumor microenvironment (TME) which plays a critical role in regulating the immune response to the tumor. Understanding the mechanisms underlying this interaction is crucial to optimizing the efficiency of ICIs. Electrochemotherapy (ECT) has been shown to enhance the efficacy of ICIs in melanoma treatment by inducing tumor cell death and facilitating the release of tumor antigens which can subsequently be recognized and targeted by the immune system. Moreover, ECT has been reported to modulate the TME, leading to increased infiltration of immune cells and a more favorable immunological profile. In this review, we summarize the available knowledge of changes in TME after ECT of melanoma cutaneous metastasis and highlight the differences in tumor-infiltrating immune cells between immunocompetent and immunosuppressed organisms. In addition, we showed that ECT can be an effective and safe procedure for organ transplant recipients. Furthermore, repeated ECT may enhance immune activation and probably induce a bystander effect by trained immunity. Full article

(This article belongs to the Special Issue Advances in Melanoma Immunotherapy and Molecular Mechanisms of Drug Resistance)

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17 pages, 1623 KiB

Open AccessReview

Metastatic Melanoma: Liquid Biopsy as a New Precision Medicine Approach

by Elena Ricciardi, Elena Giordani, Giovanna Ziccheddu, Italia Falcone, Patrizio Giacomini, Maurizio Fanciulli, Michelangelo Russillo, Marianna Cerro, Gennaro Ciliberto, Aldo Morrone, Antonino Guerrisi and Fabio Valenti

Int. J. Mol. Sci. 2023, 24(4), 4014; https://doi.org/10.3390/ijms24044014 - 16 Feb 2023

Cited by 17 | Viewed by 3771

Abstract

Precision medicine has driven a major change in the treatment of many forms of cancer. The discovery that each patient is different and each tumor mass has its own characteristics has shifted the focus of basic and clinical research to the singular individual. [...] Read more.

Precision medicine has driven a major change in the treatment of many forms of cancer. The discovery that each patient is different and each tumor mass has its own characteristics has shifted the focus of basic and clinical research to the singular individual. Liquid biopsy (LB), in this sense, presents new scenarios in personalized medicine through the study of molecules, factors, and tumor biomarkers in blood such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes and circulating tumor microRNAs (ct-miRNAs). Moreover, its easy application and complete absence of contraindications for the patient make this method applicable in a great many fields. Melanoma, given its highly heterogeneous characteristics, is a cancer form that could significantly benefit from the information linked to liquid biopsy, especially in the treatment management. In this review, we will focus our attention on the latest applications of liquid biopsy in metastatic melanoma and possible developments in the clinical setting. Full article

(This article belongs to the Special Issue Advances in Melanoma Immunotherapy and Molecular Mechanisms of Drug Resistance)

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19 pages, 1800 KiB

Open AccessReview

Phenotype Switching and the Melanoma Microenvironment; Impact on Immunotherapy and Drug Resistance

by Sultana Mehbuba Hossain and Michael R. Eccles

Int. J. Mol. Sci. 2023, 24(2), 1601; https://doi.org/10.3390/ijms24021601 - 13 Jan 2023

Cited by 19 | Viewed by 4529

Abstract

Melanoma, a highly heterogeneous tumor, is comprised of a functionally diverse spectrum of cell phenotypes and subpopulations, including stromal cells in the tumor microenvironment (TME). Melanoma has been shown to dynamically shift between different transcriptional states or phenotypes. This is referred to as [...] Read more.

Melanoma, a highly heterogeneous tumor, is comprised of a functionally diverse spectrum of cell phenotypes and subpopulations, including stromal cells in the tumor microenvironment (TME). Melanoma has been shown to dynamically shift between different transcriptional states or phenotypes. This is referred to as phenotype switching in melanoma, and it involves switching between quiescent and proliferative cell cycle states, and dramatic shifts in invasiveness, as well as changes in signaling pathways in the melanoma cells, and immune cell composition in the TME. Melanoma cell plasticity is associated with altered gene expression in immune cells and cancer-associated fibroblasts, as well as changes in extracellular matrix, which drive the metastatic cascade and therapeutic resistance. Therefore, resistance to therapy in melanoma is not only dependent on genetic evolution, but it has also been suggested to be driven by gene expression changes and adaptive phenotypic cell plasticity. This review discusses recent findings in melanoma phenotype switching, immunotherapy resistance, and the balancing of the homeostatic TME between the different melanoma cell subpopulations. We also discuss future perspectives of the biology of neural crest-like state(s) in melanoma. Full article

(This article belongs to the Special Issue Advances in Melanoma Immunotherapy and Molecular Mechanisms of Drug Resistance)

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34 pages, 3887 KiB

Open AccessReview

Shaping the Future of Immunotherapy Targets and Biomarkers in Melanoma and Non-Melanoma Cutaneous Cancers

by Pavlina Spiliopoulou, Olga Vornicova, Sofia Genta and Anna Spreafico

Int. J. Mol. Sci. 2023, 24(2), 1294; https://doi.org/10.3390/ijms24021294 - 9 Jan 2023

Cited by 8 | Viewed by 3961

Abstract

Recent advances in treating cutaneous melanoma have resulted in impressive patient survival gains. Refinement of disease staging and accurate patient risk classification have significantly improved our prognostic knowledge and ability to accurately stratify treatment. Undoubtedly, the most important step towards optimizing patient outcomes [...] Read more.

Recent advances in treating cutaneous melanoma have resulted in impressive patient survival gains. Refinement of disease staging and accurate patient risk classification have significantly improved our prognostic knowledge and ability to accurately stratify treatment. Undoubtedly, the most important step towards optimizing patient outcomes has been the advent of cancer immunotherapy, in the form of immune checkpoint inhibition (ICI). Immunotherapy has established its cardinal role in the management of both early and late-stage melanoma. Through leveraging outcomes in melanoma, immunotherapy has also extended its benefit to other types of skin cancers. In this review, we endeavor to summarize the current role of immunotherapy in melanoma and non-melanoma skin cancers, highlight the most pertinent immunotherapy-related molecular biomarkers, and lastly, shed light on future research directions. Full article

(This article belongs to the Special Issue Advances in Melanoma Immunotherapy and Molecular Mechanisms of Drug Resistance)

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11 pages, 587 KiB

Open AccessReview

Tissue Biomarkers Predicting Lymph Node Status in Cutaneous Melanoma

by Giulio Rizzetto, Guendalina Lucarini, Edoardo De Simoni, Elisa Molinelli, Monica Mattioli-Belmonte, Annamaria Offidani and Oriana Simonetti

Int. J. Mol. Sci. 2023, 24(1), 144; https://doi.org/10.3390/ijms24010144 - 21 Dec 2022

Cited by 6 | Viewed by 2089

Abstract

Cutaneous melanoma is a severe neoplasm that shows early invasiveness of the lymph nodes draining the primary site, with increased risk of distant metastases and recurrence. The tissue biomarker identification could be a new frontier to predict the risk of early lymph node [...] Read more.

Cutaneous melanoma is a severe neoplasm that shows early invasiveness of the lymph nodes draining the primary site, with increased risk of distant metastases and recurrence. The tissue biomarker identification could be a new frontier to predict the risk of early lymph node invasiveness, especially in cases considered by current guidelines to be at low risk of lymph node involvement and not requiring evaluation of the sentinel lymph node (SLN). For this reason, we present a narrative review of the literature, seeking to provide an overview of current tissue biomarkers, particularly vascular endothelium growth factors (VEGF), Tetraspanin CD9, lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), D2-40, and gene expression profile test (31-GEP). Among these, 31-GEP seems to be able to provide a distinction between low or high risk for positive SLN classes. VEGF receptor-3 and CD9 expression may be independent predictors of positive SLN. Lastly, LYVE-1 and D2-40 allow an easier assessment of lymph vascular invasion, which can be considered a good predictor of SLN status. In conclusion, biomarkers to assess the lymph node status of cutaneous melanoma patients may play an important role in those cases where the clinician is in doubt whether or not to perform SLN biopsy. Full article

(This article belongs to the Special Issue Advances in Melanoma Immunotherapy and Molecular Mechanisms of Drug Resistance)

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