Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA255097 | ENA |
REPOSITORIES: ENA
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Project description:Immunotherapy and targeted therapy dramatically changed the treatment of metastatic melanoma. Yet, many patients do not respond to these treatments and improve the understanding of response and resistance is an urgent need. Thus, we utilized mass spectrometry-based proteomic analysis of 185 metastatic melanoma samples. Metastases from different sites demonstrate differences in cellular processes such as immune, metabolism, translation and proliferation. Complementary epidemiology analysis uncovers prognosis variance between different metastases locations after treated with anti-PD1. Examination of lung melanoma metastases reveals clinical and molecular heterogeneity that mainly reflected in immune-related processes. Analysis of BRAF mutation status and prior treatments with MAPK inhibitors also indicate differences in immune and metabolic processes and suggest a molecular basis for the combination of immunotherapy and targeted therapy. These results shed new light into biology and therapeutic resistant mechanisms and the pathogenesis of metastatic melanoma.
2020-12-23 | PXD020618 | Pride
Project description:Liquid biopsies are becoming imperative on early patient diagnosis, prognosis and evaluation of residual disease. The use of circulating extracellular vesicles (EVs) as surrogate markers of tumor progression could be a powerful tool in the clinical setting. EVs in plasma have emerged as a non-invasive option to detect metastatic outcome, however sensitivity is low. Here we have characterized the lymph obtained after postoperative lymphadenectomy as a novel biological fluid enriched in EVs. Our proteomic profiling and BRAFV600E/K status determination demonstrate for the first time that EVs from the lymph of melanoma patients are enriched in melanoma-associated proteins and are useful for BRAF mutations detection. Melanoma oncogenic pathways, immunomodulation and platelet activating proteins are enriched in lymph-derived exosomes from patients with distal lymph node spread compared to local/early spreading. Furthermore, patients positive for BRAFV600E mutation on lymph-circulating vesicles had a shorter time of relapse. These data encourage the analysis of lymph-circulating EVs for detection of residual disease and recurrence.
2019-03-13 | PXD012042 | Pride
Project description:In order to improve our understanding of microRNA (miRNA) deregulation in melanoma development and possible consequences for patient survival, miRNA expression profiles were determined, using an array based approach, in melanoma tumors, melanoma cell lines and normal melanocytes. Differentially expressed miRNAs were evaluated in relation to clinical characteristics, patient prognosis in terms of melanoma-specific survival, and mutational status for BRAF and NRAS.
2010-04-21 | GSE19387 | GEO
Project description:Liquid biopsies are becoming imperative on early patient diagnosis, prognosis and evaluation of residual disease. The use of circulating extracellular vesicles (EVs) as surrogate markers of tumor progression could be a powerful tool in the clinical setting. EVs in plasma have emerged as a non-invasive option to detect metastatic outcome, however sensitivity is low. Here we have characterized the lymph obtained after postoperative lymphadenectomy as a novel biological fluid enriched in EVs. Our proteomic profiling and BRAFV600E/K status determination demonstrate for the first time that EVs from the lymph of melanoma patients are enriched in melanoma-associated proteins and are useful for BRAF mutations detection. Melanoma oncogenic pathways, immunomodulation and platelet activating proteins are enriched in lymph-derived exosomes from patients with distal lymph node spread compared to local/early spreading. Furthermore, patients positive for BRAFV600E mutation on lymph-circulating vesicles had a shorter time of relapse. These data encourage the analysis of lymph-circulating EVs for detection of residual disease and recurrence.ADDENDUM: After the proper verification of the cell lines analysed in this dataset where it is written "SKMel103" or "SK103", it should be read as "SKMel147". This affects not only the raw files but also all the search results files. Sorry for the inconveniences.
2021-02-26 | PXD009505 | Pride
Project description:A panel of 17 human melanoma cell lines with known BRAF and NRAS mutation status was stimulated with TNF-alpha for 72 hours. The goal of the study was to correlate the transcriptional response in BRAF versus NRAS mutated melanoma cell lines.
2014-02-10 | GSE51221 | GEO
Project description:Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identified bona fide activating mutations in RAC1, with mutations of its upstream regulator, the RAC-GEF PREX2, also commonly detected. Crucially, RAC1 mutations are associated with resistance to BRAF-targeting therapies. Despite the role of its homologue PREX1 in melanomagenesis, and evidence that some truncating PREX2 mutations drive increased RAC1 activity, no hotspot mutations have been identified, and the impact of PREX2 mutation remains contentious. Here, we use genetically engineered mouse models and patient-derived BRAFV600E-driven melanoma cell lines to dissect the role of PREX2 in melanomagenesis and response to therapy. We show that while PREX2 is dispensable for the initiation and progression of melanoma, its loss confers sensitivity to clinically relevant therapeutics. Importantly, genetic and pharmacological targeting of the RAC1 effector kinase PI3Kβ phenocopies PREX2 loss, sensitizing our model systems to therapy. Our data reveal a druggable PREX2/RAC1/PI3Kβ signalling axis in BRAF-mutant melanoma that could be exploited clinically.
2024-11-22 | GSE281123 | GEO
Project description:To determine how mutation of BRAF affected the response to RAF265, we utilized a tumor orthotopic implant model of early passage melanoma tumors in nude mice from a series of 17 patients with advanced metastatic Tumor growth was compared between RAF265 treatment (40 mg/kg, QD) and diluent control groups. The melanoma associated gene mutation profile and global gene expression profile were determined on these human melanoma samples by SNaPshot and Affymetrix Human Gene ST 1.0 Array, respectively. Tumors were evaluated for growth response to RAF265 in an orthotopic implant model using nude mice. Comparisons were made between gene expression profiles of responders and non-responders, BRAF mutant and BRAF wild type tumors. Analysis of the microarray data revealed responders exhibited enriched expression of genes involved in cell cycle, apoptosis, cell-cell adhesion and initiation of epithelial/mesenchymal transition. It is concluded that RAF265 significantly inhibits the growth of a sub-population of V600E mutant and wild type BRAF human melanoma tumors in vivo and the gene expression profile of this subset of tumors that may predict response to RAF265. RNA from 17 human metastatic melanoma tumors was extracted and hybridized on Affymetrix microarrays.
2012-05-01 | E-GEOD-30812 | biostudies-arrayexpress
Project description:In order to improve our understanding of microRNA (miRNA) deregulation in melanoma development and possible consequences for patient survival, miRNA expression profiles were determined, using an array based approach, in melanoma tumors, melanoma cell lines and normal melanocytes. Differentially expressed miRNAs were evaluated in relation to clinical characteristics, patient prognosis in terms of melanoma-specific survival, and mutational status for BRAF and NRAS. Agilent microarray platform containing 470 miRNAs was used to determine miRNA expression profiles in 3 normal melanocytes (as non-neoplastic control), 21 melanoma cell lines and 16 clinical samples from fresh frozen regional lymph node metastases. To validate the microarray platform, the expression levels of some miRNAs were evaluated using RT-PCR and the correlation between the two platforms was assessed using Pearson Correlation analysis. The results obtained were further verified and confirmed by RT-PCR in an independent set of melanoma samples. Association between deregulated miRNAs and survival was determined by Univariate Cox proportional hazards model and log rank test.
2010-04-21 | E-GEOD-19387 | biostudies-arrayexpress
Project description:A panel of 17 human melanoma cell lines with known BRAF and NRAS mutation status was stimulated with TNF-alpha for 72 hours. The goal of the study was to correlate the transcriptional response in BRAF versus NRAS mutated melanoma cell lines. Total RNA was obtained from a panel of 17 human melanoma cell lines treated for 72 hours with TNF-alpha or left untreated. Gene expression profiling was done using the Illumina Human HT12 v4 platform.
2014-02-10 | E-GEOD-51221 | biostudies-arrayexpress
Project description:<p>Dysregulated kinase activity drives oncogenic signalling, perturbs cellular homeostasis, and promotes tumour progression. Despite major success in targeting kinases therapeutically, the downstream consequences of kinase inhibition and the mechanisms underlying drug resistance remain incompletely understood. One of the most frequent oncogenic kinase mutations, BRAFV600E, constitutively activates the MAPK pathway and represents a major therapeutic target in melanoma and other cancers. However, the functional relevance of most phosphorylation events downstream of BRAF signalling is unknown, limiting mechanistic interpretation and rational therapeutic design.</p><p> Here, we established a global, multi-omic model of BRAF inhibition response in BRAFV600E-mutant melanoma cells by integrating time-resolved phosphoproteomics, biophysical PTM-proteomics, transcriptomics, and thermal proteome profiling. Our ultradeep phosphoproteomic analysis revealed widespread phosphorylation changes upon Dabrafenib treatment, while biophysical phosphoproteomics uncovered phosphorylation events associated with altered solubility and subcellular localisation, indicative of biomolecular condensation and nuclear reorganisation. Integration of these modalities into a network-based mechanistic model enabled the prioritisation of functionally relevant phosphorylation sites and kinases. Experimental validation confirmed CDK9, CLK3, and TNIK as key regulators of BRAFV600E signalling and as candidate targets for combinatorial inhibition strategies capable of re-sensitising resistant melanoma cells in a synthetic lethal manner.</p><p> The transcription factor ETV3 emerged from the network as a previously unrecognised effector of oncogenic BRAF signalling. Using phosphosite-specific biophysical data, imaging, and FRAP experiments, we demonstrated that ETV3 phosphorylation controls its DNA-binding kinetics. Functional assays combining ETV3 knockdown, metabolomics, and drug screening revealed that ETV3 modulates transcriptional and metabolic responses to BRAF inhibition, linking oncogenic signalling to metabolic rewiring.</p><p> Together, this study provides a comprehensive systems-level framework that connects phosphorylation dynamics to protein function and cellular phenotype, highlights ETV3 as a novel signalling node, and illustrates how multi-omic, site-resolved network models can reveal actionable mechanisms of kinase-driven oncogenesis.</p>
2025-12-09 | MTBLS7390 | MetaboLights