Uveal Melanoma zebrafish xenograft models illustrate the mutation status-dependent effect of compound synergism or antagonism DOI Creative Commons

Quincy van den Bosch,

Emine Kılıç, Erwin Brosens

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: April 24, 2024

Abstract Purpose Uveal melanoma (UM) is the most common primary intraocular malignancy with a high probability of metastatic disease. Although excellent treatment option for UM are available, therapy disease remain limited. Drug discovery studies using mouse models have thus far failed to provide therapeutic solutions, highlighting need novel models. Here, we optimize zebrafish xenografts as potential model drug by showcasing behavior multiple cell lines and findings on mutation-dependent compound synergism/antagonism Z-Tada; an algorithm objectively characterize output measurements. Methods Prognostic relevant or healthy melanocytes were inoculated at three distinct inoculation sites. Standardized quantifications independent site obtained measure tumor burden number, size distance disseminated cells. Sequentially, utilized this validate combinatorial synergism antagonism seen in vitro. Results Detailed analysis 691 demonstrated perivitelline space provided robust data dissemination. Cell more invasive (SF3B1mut BAP1mut) behaved aggressive in model. Combinatorial illustrated mutation-dependent, which confirmed vivo. differed per xenograft-model, it either inhibited overall Conclusion Perivitelline provides ability high-throughput screening acquisition Z-Tada. This demonstrates that uveal must take mutational subclasses into account, especially discoveries.

Language: Английский

Ergolide mediates anti-cancer effects on metastatic uveal melanoma cells and modulates their cellular and extracellular vesicle proteomes DOI Creative Commons
Husvinee Sundaramurthi, Valentina Tonelotto, Kieran Wynne

et al.

Open Research Europe, Journal Year: 2023, Volume and Issue: 3, P. 88 - 88

Published: Nov. 13, 2023

Background Uveal melanoma is a poor prognosis cancer. Ergolide, sesquiterpene lactone isolated from Inula Brittanica, exerts anti-cancer properties. The objective of this study was to 1) evaluate whether ergolide reduced metastatic uveal (MUM) cell survival/viability in vitro and vivo; 2) understand the molecular mechanism action. Methods Ergolide bioactivity screened via long-term proliferation assay in UM/MUM cells zebrafish MUM xenograft models. Mass spectrometry profiled proteins modulated by within whole or extracellular vesicle (EVs) lysates OMM2.5 line. Protein expression analyzed immunoblots correlation analyses UM patient survival used Cancer Genome Atlas (TCGA) data. Results treatment resulted significant, dose-dependent reductions (48.5 99.9%; p<0.0001) normalized primary fluorescence (56%; vivo, compared vehicle controls. Proteome-profiling ergolide-treated cells, identified 5023 proteins, with 52 55 significantly altered at 4 24 hours, respectively (p<0.05; fold-change >1.2). Immunoblotting heme oxygenase 1 (HMOX1) growth/differentiation factor 15 (GDF15) corroborated proteomic Additional proteomics EVs treated ergolide, detected 2931 proteins. There large overlap EV annotated Vesiclepedia compendium. Within differentially expressed proteasomal pathway primarily altered. Interestingly, BRCA2 CDKN1A Interacting (BCCIP) Chitinase Domain Containing (CHID1), were only both cellular isolates they displayed inverse differential versus EVs. Conclusions novel, promising anti-proliferative agent for UM/MUM. Proteomic profiling cellular/EV candidate pathways elucidating action putative biomarkers UM, that require further examination.

Language: Английский

Citations

5
Recent Advances in Molecular and Genetic Research on Uveal Melanoma DOI Creative Commons
Aurélie Fuentes-Rodriguez,

Andrew Mitchell,

Sylvain L. Guérin

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(12), P. 1023 - 1023

Published: June 12, 2024

Uveal melanoma (UM), a distinct subtype of melanoma, presents unique challenges in its clinical management due to complex molecular landscape and tendency for liver metastasis. This review highlights recent advancements understanding the pathogenesis, genetic alterations, immune microenvironment UM, with focus on pivotal genes, such as GNAQ/11, BAP1, CYSLTR2, delves into distinctive chromosomal classifications emphasizing role mutations rearrangements disease progression metastatic risk. Novel diagnostic biomarkers, including circulating tumor cells, DNA extracellular vesicles, are discussed, offering potential non-invasive approaches early detection monitoring. It also explores emerging prognostic markers their implications patient stratification personalized treatment strategies. Therapeutic approaches, histone deacetylase inhibitors, MAPK pathway trends concepts like CAR T-cell therapy, evaluated efficacy UM treatment. identifies research, limited options need improved tools, suggests future directions, discovery novel therapeutic targets, immunotherapeutic strategies, advanced drug delivery systems. The concludes by importance continued research innovation addressing improve outcomes develop more effective

Language: Английский

Citations

1
Uveal Melanoma Zebrafish Xenograft Models Illustrate the Mutation Status-Dependent Effect of Compound Synergism or Antagonism DOI Creative Commons
Quincy C. C. van den Bosch, Emine Kılıç, Erwin Brosens

et al.

Investigative Ophthalmology & Visual Science, Journal Year: 2024, Volume and Issue: 65(10), P. 26 - 26

Published: Aug. 20, 2024

Uveal melanoma (UM) is the most common primary intraocular malignancy with a high probability of metastatic disease. Although excellent treatment options for UM are available, therapy disease remain limited. Drug discovery studies using mouse models have thus far failed to provide therapeutic solutions, highlighting need novel models. Here, we optimize zebrafish xenografts as potential model drug by showcasing behavior multiple cell lines and findings on mutation-dependent compound synergism/antagonism Z-Tada; an algorithm objectively characterize output measurements.

Language: Английский

Citations

1
Pharmacological drug screening to inhibit uveal melanoma metastatic cells either via EGF-R, MAPK, mTOR or PI3K DOI Creative Commons
Stefan Kassumeh,

André Kafka,

Nikolaus Luft

et al.

International Journal of Ophthalmology, Journal Year: 2022, Volume and Issue: 15(10), P. 1569 - 1576

Published: Sept. 22, 2022

To screen five potential pharmacological substances specifically targeting EGF-R, MAPK, mTOR, or PI3K for their antiproliferative effects, possible impact on cell viability, as well death rates three different uveal melanoma metastasis lines in vitro.Three (OMM2.5, OMM2.3, and OMM1), that originated from human hepatic subcutaneous metastasis, were exposed to inhibitors of targets: erlotinib (EGF-R), everolimus (mTOR), selumetinib (MAPK), trametinib (MAPK) the alkylphosphocholine erufosine (PI3K). Cell viability was assessed with a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) dye reduction assay after 24h treatment. Antiproliferative effects evaluated separately 72-hour incubation cells substance. Subsequently, IC50 calculated. Tumor investigated using double stain apoptosis detection assay.Selumetinib, trametinib, significantly decreased all OMM (P<0.04). In addition, showed significant inhibition proliferation (P<0.05). Everolimus solely inhibited at used concentrations Besides an increase necrotic treatment (P<0.001), no changes number dead other observed.The preliminary drug screening demonstrates new candidates, successfully canonical MAPK/ERK PI3K/AKT/mTOR pathways vitro. Hence, these findings provide experimental basis explore future single combined therapy strategies metastatic melanoma.

Language: Английский

Citations

6
Uveal melanoma modeling in mice and zebrafish DOI Creative Commons
Quincy C. C. van den Bosch, Annelies de Klein, Robert M. Verdijk

et al.

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2023, Volume and Issue: 1879(1), P. 189055 - 189055

Published: Dec. 15, 2023

Despite extensive research and refined therapeutic options, the survival for metastasized uveal melanoma (UM) patients has not improved significantly. UM, a malignant tumor originating from melanocytes in tract, can be asymptomatic small tumors may detected only during routine ophthalmic exams; making early detection treatment difficult. UM is result of number characteristic somatic alterations which are associated with prognosis. Although morphology biology have been extensively studied, there significant gaps our understanding stages evolution effective to prevent metastatic disease remain elusive. A better mechanisms that enable cells thrive successfully metastasize crucial improve efficacy rates. For more than forty years, animal models used investigate UM. This led essential pathways involved aetiology. These also evaluate effectiveness various drugs protocols. Here, we provide an overview molecular pharmacological studies using mouse zebrafish models. Finally, highlight promising therapeutics discuss future considerations such as optimal inoculation sites, use BAP1mut-cell lines rise

Language: Английский

Citations

3
Evaluation of the Therapeutic Potential of Histone Deacetylase 6 Inhibitors for Primary and Metastatic Uveal Melanoma DOI Open Access
Husvinee Sundaramurthi, Zoltán Giricz, Breandán N. Kennedy

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(16), P. 9378 - 9378

Published: Aug. 19, 2022

Patients diagnosed with metastatic uveal melanoma (MUM) have a poor survival prognosis. Unfortunately for this rare disease, there is no known cure and suitable therapeutic options are limited. HDAC6 inhibitors (HDAC6i) currently in clinical trials other cancers show potential beneficial effects against tumor cell vitro vivo. In MUM cells, HDAC6i an anti-proliferative effect preclinical xenograft models. The use of as treatment option should be explored further. Therefore, review discusses (1) what about (2) whether offer MUM.

Language: Английский

Citations

4
Ergolide mediates anti-cancer effects on metastatic uveal melanoma cells and modulates their cellular and extracellular vesicle proteomes DOI Creative Commons
Husvinee Sundaramurthi, Valentina Tonelotto, Kieran Wynne

et al.

Open Research Europe, Journal Year: 2023, Volume and Issue: 3, P. 88 - 88

Published: June 8, 2023

Background: Uveal melanoma is a poor prognosis cancer. Ergolide, sesquiterpene lactone isolated from Inula Brittanica, exerts anti-cancer properties. The objective of this study was to 1) evaluate whether ergolide reduced metastatic uveal (MUM) cell survival/viability in vitro and vivo; 2) understand the molecular mechanism action. Methods: Ergolide bioactivity screened via long-term proliferation assay in UM/MUM cells zebrafish MUM xenograft models. Mass spectrometry profiled proteins modulated by within whole or extracellular vesicle (EVs) lysates OMM2.5 line. Protein expression analyzed immunoblots correlation analyses UM patient survival used Cancer Genome Atlas (TCGA) data. Results: Ergolide treatment resulted significant, dose-dependent reductions (48.5 99.9%; p<0.0001) normalized primary fluorescence (56%; vivo, compared vehicle controls. Proteome-profiling ergolide-treated cells, identified 5023 proteins, with 52 55 significantly altered at 4 24 hours, respectively (p<0.05; fold-change >1.2). Immunoblotting heme oxygenase 1 (HMOX1) growth/differentiation factor 15 (GDF15) corroborated proteomic data. Additional proteomics EVs treated ergolide, detected 2931 proteins. There large overlap EV annotated Vesiclepedia compendium. Within differentially expressed proteasomal pathway primarily altered. Interestingly, BRCA2 CDKN1A Interacting (BCCIP) Chitinase Domain Containing (CHID1), were only both cellular isolates they displayed inverse differential versus EVs. Conclusions: novel, promising anti-proliferative agent for UM/MUM. Proteomic profiling cellular/EV candidate pathways elucidating action putative biomarkers UM, that require further examination.

Language: Английский

Citations

2
Uveal Melanoma: Molecular and Genetic Mechanisms of Development and Therapeutic Approaches DOI

M.V. Zhilnikova,

Olga Troitskaya,

D. D. Novak

et al.

Molecular Biology, Journal Year: 2024, Volume and Issue: 58(2), P. 165 - 177

Published: April 1, 2024

Language: Английский

Citations

0
Assessment of ferroptosis as a promising candidate for metastatic uveal melanoma treatment and prognostication DOI Creative Commons

Ellie Swords,

Breandán N. Kennedy, Valentina Tonelotto

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Oct. 1, 2024

Uveal melanoma (UM) is the most common primary intraocular tumour in adults. Local resection, radiation therapy, and enucleation are current first-line, UM treatments. However, regardless of treatment received, around 50% patients will develop metastatic disease within five to 7 years. In largest published series unselected with (mUM), median survival time after diagnosis metastasis was 3.6 months, less than 1% surviving beyond 5 Approved drugs for mUM include systemic tebentafusp-tebn or isolated hepatic perfusion (IHP) melphalan. these only available a subset improve by few highlighting urgent need new Accurately predicting which at high risk metastases also crucial. Researchers developing gene expression signatures create reliable prognostic models aimed improving patient follow-up strategies. this review we discuss evidence supporting ferroptosis, non-apoptotic form cell death, as potential novel target prognosticator UM.

Language: Английский

Citations

0
Uveal melanoma: molecular-genetic mechanisms of arising and the therapeutic approaches DOI

Maria Zhilnikova,

Olga Troitskaya,

D. D. Novak

et al.

Молекулярная биология, Journal Year: 2024, Volume and Issue: 58(2), P. 189 - 203

Published: Oct. 9, 2024

Uveal melanoma (UM) is a neuroectodermal tumor that results from malignant transformation of melanocytes in the eye uvea, including iris, ciliary body, and choroid. UM accounts for 5% all cases extremely aggressive with half patients developing metastases within first 1-2 years after development. Molecular mechanisms carcinogenesis are poorly understood, but known to differ those skin melanoma. Activating mutations GNAQ GNA11 genes, which code large G protein subunits Gq G11, respectively, found 90% patients. The Gaq/PKC/MAPK signaling pathway main cascade leads uveal tract, major regulators provide targets development drugs. Metastatic (MUM) most often associated BAP1, EIF1AX, GNA11, GNAQ, SF3B1. A combination commercial expression test panel 15 genes mutation 7 supplemented data on size primary tumor, highly efficient predicting risk metastasis. metastasis determines choice therapy patient follow-up regimen. However, no systemic MUM has been developed date. New drugs undergoing clinical trials mostly targeted designed inhibit products mutant or immunotherapeutic agents stimulate immune response against specific antigens. In addition these approaches, potential therapeutic epigenetic regulation considered review.

Language: Английский

Citations

0