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22 pages, 6785 KiB

Open AccessArticle

BRAF-Mutated Melanoma Cell Lines Develop Distinct Molecular Signatures After Prolonged Exposure to AZ628 or Dabrafenib: Potential Benefits of the Antiretroviral Treatments Cabotegravir or Doravirine on BRAF-Inhibitor-Resistant Cells

by Valentina Zanrè, Francesco Bellinato, Alessia Cardile, Carlotta Passarini, Stefano Di Bella and Marta Menegazzi

Int. J. Mol. Sci. 2024, 25(22), 11939; https://doi.org/10.3390/ijms252211939 - 6 Nov 2024

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Abstract

Melanoma is an aggressive cancer characterized by rapid growth, early metastasis, and poor prognosis, with resistance to current therapies being a significant issue. BRAF mutations drive uncontrolled cell division by activating the MAPK pathway. In this study, A375 and FO-1, BRAF-mutated melanoma cell [...] Read more.

Melanoma is an aggressive cancer characterized by rapid growth, early metastasis, and poor prognosis, with resistance to current therapies being a significant issue. BRAF mutations drive uncontrolled cell division by activating the MAPK pathway. In this study, A375 and FO-1, BRAF-mutated melanoma cell lines, were treated for 4–5 months with RAF inhibitor dabrafenib or AZ628, leading to drug resistance over time. The resistant cells showed altered molecular signatures, with differences in cell cycle regulation and the propensity of cell death. Dabrafenib-resistant cells maintained high proliferative activity, while AZ628-resistant cells, especially A375 cells, exhibited slow-cycling, and a senescent-like phenotype with high susceptibility to ferroptosis, a form of cell death driven by iron. Antiretroviral drugs doravirine and cabotegravir, known for their effects on human endogenous retroviruses, were tested for their impact on these resistant melanoma cells. Both drugs reduced cell viability and colony formation in resistant cell lines. Doravirine was particularly effective in reactivating apoptosis and reducing cell growth in highly proliferative resistant cells by increasing tumor-suppressor proteins p16^Ink4a and p27^Kip1. These findings suggest that antiretroviral drugs can influence apoptosis and cell proliferation in RAF-inhibitor-resistant melanoma cells, offering potential therapeutic strategies for overcoming drug resistance. Full article

(This article belongs to the Special Issue Melanoma: From Molecular Pathology to Therapeutic Approaches)

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19 pages, 6380 KiB

Open AccessArticle

Quercetin Impairs the Growth of Uveal Melanoma Cells by Interfering with Glucose Uptake and Metabolism

by Aysegül Tura, Viktoria Herfs, Tjorge Maaßen, Huaxin Zuo, Siranush Vardanyan, Michelle Prasuhn, Mahdy Ranjbar, Vinodh Kakkassery and Salvatore Grisanti

Int. J. Mol. Sci. 2024, 25(8), 4292; https://doi.org/10.3390/ijms25084292 - 12 Apr 2024

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Abstract

Monosomy 3 in uveal melanoma (UM) increases the risk of lethal metastases, mainly in the liver, which serves as the major site for the storage of excessive glucose and the metabolization of the dietary flavonoid quercetin. Although primary UMs with monosomy 3 exhibit [...] Read more.

Monosomy 3 in uveal melanoma (UM) increases the risk of lethal metastases, mainly in the liver, which serves as the major site for the storage of excessive glucose and the metabolization of the dietary flavonoid quercetin. Although primary UMs with monosomy 3 exhibit a higher potential for basal glucose uptake, it remains unknown as to whether glycolytic capacity is altered in such tumors. Herein, we initially analyzed the expression of n = 151 genes involved in glycolysis and its interconnected branch, the “pentose phosphate pathway (PPP)”, in the UM cohort of The Cancer Genome Atlas Study and validated the differentially expressed genes in two independent cohorts. We also evaluated the effects of quercetin on the growth, survival, and glucose metabolism of the UM cell line 92.1. The rate-limiting glycolytic enzyme PFKP was overexpressed whereas the ZBTB20 gene (locus: 3q13.31) was downregulated in the patients with metastases in all cohorts. Quercetin was able to impair proliferation, viability, glucose uptake, glycolysis, ATP synthesis, and PPP rate-limiting enzyme activity while increasing oxidative stress. UMs with monosomy 3 display a stronger potential to utilize glucose for the generation of energy and biomass. Quercetin can prevent the growth of UM cells by interfering with glucose metabolism. Full article

(This article belongs to the Special Issue Melanoma: From Molecular Pathology to Therapeutic Approaches)

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14 pages, 3758 KiB

Open AccessArticle

Endothelial Mitochondria Transfer to Melanoma Induces M2-Type Macrophage Polarization and Promotes Tumor Growth by the Nrf2/HO-1-Mediated Pathway

by Fu-Chen Kuo, Hsin-Yi Tsai, Bi-Ling Cheng, Kuen-Jang Tsai, Ping-Chen Chen, Yaw-Bin Huang, Chung-Jung Liu, Deng-Chyang Wu, Meng-Chieh Wu, Bin Huang and Ming-Wei Lin

Int. J. Mol. Sci. 2024, 25(3), 1857; https://doi.org/10.3390/ijms25031857 - 3 Feb 2024

Cited by 1 | Viewed by 1991

Abstract

Gynecologic tract melanoma is a malignant tumor with poor prognosis. Because of the low survival rate and the lack of a standard treatment protocol related to this condition, the investigation of the mechanisms underlying melanoma progression is crucial to achieve advancements in the [...] Read more.

Gynecologic tract melanoma is a malignant tumor with poor prognosis. Because of the low survival rate and the lack of a standard treatment protocol related to this condition, the investigation of the mechanisms underlying melanoma progression is crucial to achieve advancements in the relevant gynecological surgery and treatment. Mitochondrial transfer between adjacent cells in the tumor microenvironment regulates tumor progression. This study investigated the effects of endothelial mitochondria on the growth of melanoma cells and the activation of specific signal transduction pathways following mitochondrial transplantation. Mitochondria were isolated from endothelial cells (ECs) and transplanted into B16F10 melanoma cells, resulting in the upregulation of proteins associated with tumor growth. Furthermore, enhanced antioxidation and mitochondrial homeostasis mediated by the Sirt1-PGC-1α-Nrf2-HO-1 pathway were observed, along with the inhibition of apoptotic protein caspase-3. Finally, the transplantation of endothelial mitochondria into B16F10 cells promoted tumor growth and increased M2-type macrophages through Nrf2/HO-1-mediated pathways in a xenograft animal model. In summary, the introduction of exogenous mitochondria from ECs into melanoma cells promoted tumor growth, indicating the role of mitochondrial transfer by stromal cells in modulating a tumor’s phenotype. These results provide valuable insights into the role of mitochondrial transfer and provide potential targets for gynecological melanoma treatment. Full article

(This article belongs to the Special Issue Melanoma: From Molecular Pathology to Therapeutic Approaches)

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16 pages, 1585 KiB

Open AccessArticle

Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells

by Zhi Liu, Aleksandar Krstic, Ashish Neve, Cristina Casalou, Nora Rauch, Kieran Wynne, Hilary Cassidy, Amanda McCann, Emma Kavanagh, Brendan McCann, Alfonso Blanco, Jens Rauch and Walter Kolch

Int. J. Mol. Sci. 2023, 24(14), 11821; https://doi.org/10.3390/ijms241411821 - 23 Jul 2023

Cited by 2 | Viewed by 2716

Abstract

Kinase Suppressor of RAS 1 (KSR1) is a scaffolding protein for the RAS-RAF-MEK-ERK pathway, which is one of the most frequently altered pathways in human cancers. Previous results have shown that KSR1 has a critical role in mutant RAS-mediated transformation. Here, we examined [...] Read more.

Kinase Suppressor of RAS 1 (KSR1) is a scaffolding protein for the RAS-RAF-MEK-ERK pathway, which is one of the most frequently altered pathways in human cancers. Previous results have shown that KSR1 has a critical role in mutant RAS-mediated transformation. Here, we examined the role of KSR1 in mutant BRAF transformation. We used CRISPR/Cas9 to knock out KSR1 in a BRAFV600E-transformed melanoma cell line. KSR1 loss produced a complex phenotype characterised by impaired proliferation, cell cycle defects, decreased transformation, decreased invasive migration, increased cellular senescence, and increased apoptosis. To decipher this phenotype, we used a combination of proteomic ERK substrate profiling, global protein expression profiling, and biochemical validation assays. The results suggest that KSR1 directs ERK to phosphorylate substrates that have a critical role in ensuring cell survival. The results further indicate that KSR1 loss induces the activation of p38 Mitogen-Activated Protein Kinase (MAPK) and subsequent cell cycle aberrations and senescence. In summary, KSR1 function plays a key role in oncogenic BRAF transformation. Full article

(This article belongs to the Special Issue Melanoma: From Molecular Pathology to Therapeutic Approaches)

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Review

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16 pages, 2766 KiB

Open AccessReview

Immune Checkpoint Inhibitor Therapy for Metastatic Melanoma: What Should We Focus on to Improve the Clinical Outcomes?

by Sultana Mehbuba Hossain, Kevin Ly, Yih Jian Sung, Antony Braithwaite and Kunyu Li

Int. J. Mol. Sci. 2024, 25(18), 10120; https://doi.org/10.3390/ijms251810120 - 20 Sep 2024

Viewed by 2069

Abstract

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enhancing anti-tumour immune responses, demonstrating significant efficacy in various malignancies, including melanoma. However, over 50% of patients experience limited or no response to ICI therapy. Resistance to ICIs is influenced by a complex interplay [...] Read more.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enhancing anti-tumour immune responses, demonstrating significant efficacy in various malignancies, including melanoma. However, over 50% of patients experience limited or no response to ICI therapy. Resistance to ICIs is influenced by a complex interplay of tumour intrinsic and extrinsic factors. This review summarizes current ICIs for melanoma and the factors involved in resistance to the treatment. We also discuss emerging evidence that the microbiota can impact ICI treatment outcomes by modulating tumour biology and anti-tumour immune function. Furthermore, microbiota profiles may offer a non-invasive method for predicting ICI response. Therefore, future research into microbiota manipulation could provide cost-effective strategies to enhance ICI efficacy and improve outcomes for melanoma patients. Full article

(This article belongs to the Special Issue Melanoma: From Molecular Pathology to Therapeutic Approaches)

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18 pages, 663 KiB

Open AccessReview

Genomic and Epigenomic Biomarkers of Immune Checkpoint Immunotherapy Response in Melanoma: Current and Future Perspectives

by Sultana Mehbuba Hossain, Carien Carpenter and Michael R. Eccles

Int. J. Mol. Sci. 2024, 25(13), 7252; https://doi.org/10.3390/ijms25137252 - 30 Jun 2024

Viewed by 1752

Abstract

Immune checkpoint inhibitors (ICIs) demonstrate durable responses, long-term survival benefits, and improved outcomes in cancer patients compared to chemotherapy. However, the majority of cancer patients do not respond to ICIs, and a high proportion of those patients who do respond to ICI therapy [...] Read more.

Immune checkpoint inhibitors (ICIs) demonstrate durable responses, long-term survival benefits, and improved outcomes in cancer patients compared to chemotherapy. However, the majority of cancer patients do not respond to ICIs, and a high proportion of those patients who do respond to ICI therapy develop innate or acquired resistance to ICIs, limiting their clinical utility. The most studied predictive tissue biomarkers for ICI response are PD-L1 immunohistochemical expression, DNA mismatch repair deficiency, and tumour mutation burden, although these are weak predictors of ICI response. The identification of better predictive biomarkers remains an important goal to improve the identification of patients who would benefit from ICIs. Here, we review established and emerging biomarkers of ICI response, focusing on epigenomic and genomic alterations in cancer patients, which have the potential to help guide single-agent ICI immunotherapy or ICI immunotherapy in combination with other ICI immunotherapies or agents. We briefly review the current status of ICI response biomarkers, including investigational biomarkers, and we present insights into several emerging and promising epigenomic biomarker candidates, including current knowledge gaps in the context of ICI immunotherapy response in melanoma patients. Full article

(This article belongs to the Special Issue Melanoma: From Molecular Pathology to Therapeutic Approaches)

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30 pages, 2202 KiB

Open AccessReview

Development of Personalized Strategies for Precisely Battling Malignant Melanoma

by Armond J. Isaak, GeGe R. Clements, Rand Gabriel M. Buenaventura, Glenn Merlino and Yanlin Yu

Int. J. Mol. Sci. 2024, 25(9), 5023; https://doi.org/10.3390/ijms25095023 - 4 May 2024

Cited by 2 | Viewed by 2220

Abstract

Melanoma is the most severe and fatal form of skin cancer, resulting from multiple gene mutations with high intra-tumor and inter-tumor molecular heterogeneity. Treatment options for patients whose disease has progressed beyond the ability for surgical resection rely on currently accepted standard therapies, [...] Read more.

Melanoma is the most severe and fatal form of skin cancer, resulting from multiple gene mutations with high intra-tumor and inter-tumor molecular heterogeneity. Treatment options for patients whose disease has progressed beyond the ability for surgical resection rely on currently accepted standard therapies, notably immune checkpoint inhibitors and targeted therapies. Acquired resistance to these therapies and treatment-associated toxicity necessitate exploring novel strategies, especially those that can be personalized for specific patients and/or populations. Here, we review the current landscape and progress of standard therapies and explore what personalized oncology techniques may entail in the scope of melanoma. Our purpose is to provide an up-to-date summary of the tools at our disposal that work to circumvent the common barriers faced when battling melanoma. Full article

(This article belongs to the Special Issue Melanoma: From Molecular Pathology to Therapeutic Approaches)

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18 pages, 4085 KiB

Open AccessReview

Genetic Concordance in Primary Cutaneous Melanoma and Matched Metastasis: A Systematic Review and Meta-Analysis

by Thamila Kerkour, Catherine Zhou, Loes Hollestein and Antien Mooyaart

Int. J. Mol. Sci. 2023, 24(22), 16281; https://doi.org/10.3390/ijms242216281 - 14 Nov 2023

Cited by 2 | Viewed by 1723

Abstract

Studying primary melanoma and its corresponding metastasis has twofold benefits. Firstly, to better understand tumor biology, and secondly, to determine which sample should be examined in assessing drug targets. This study systematically analyzed all the literature on primary melanoma and its matched metastasis. [...] Read more.

Studying primary melanoma and its corresponding metastasis has twofold benefits. Firstly, to better understand tumor biology, and secondly, to determine which sample should be examined in assessing drug targets. This study systematically analyzed all the literature on primary melanoma and its matched metastasis. Following PRISMA guidelines, we searched multiple medical databases for relevant publications from January 2000 to December 2022, assessed the quality of the primary-level studies using the QUIPS tool, and summarized the concordance rate of the most reported genes using the random-effects model. Finally, we evaluated the inter-study heterogeneity using the subgroup analysis. Thirty-one studies investigated the concordance of BRAF and NRAS in 1220 and 629 patients, respectively. The pooled concordance rate was 89.4% [95% CI: 84.5; 93.5] for BRAF and 97.8% [95% CI: 95.8; 99.4] for NRAS. When high-quality studies were considered, only BRAF mutation status consistency increased. Five studies reported the concordance status of c-KIT (93%, 44 patients) and TERT promoter (64%, 53 patients). Lastly, three studies analyzed the concordance of cancer genes involved in the signaling pathways, apoptosis, and proliferation, such as CDKN2A (25%, four patients), TP53 (44%, nine patients), and PIK3CA (20%, five patients). Our study found that the concordance of known drug targets (mainly BRAF) during melanoma progression is higher than in previous meta-analyses, likely due to advances in molecular techniques. Furthermore, significant heterogeneity exists in the genes involved in the melanoma genetic makeup; although our results are based on small patient samples, more research is necessary for validation. Full article

(This article belongs to the Special Issue Melanoma: From Molecular Pathology to Therapeutic Approaches)

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