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Interfering with aggregated α-synuclein in advanced melanoma leads to a major upregulation of MHC class II proteins

ABSTRACT: Melanoma is the most serious and deadly form of skin cancer and with progression to advanced melanoma, the intrinsically disordered protein α-synuclein is upregulated to high levels; and while toxic to dopaminergic neurons in Parkinson’s disease, it is highly beneficial for primary and metastatic melanoma cells. To gain detailed insights, both at the level of the proteome and the transcriptome, into this exact opposite role of α-synuclein in advanced melanoma, we performed proteomic studies of high-level α-synuclein-expressing primary and metastatic human melanoma cell lines and proteomic and transcriptomic studies of metastatic human melanoma xenografts treated systemically with the diphenyl-pyrazole small-molecule compound anle138b, which binds to and interferes with the oligomeric structure of α-synuclein. The results of these studies reveal that interfering with oligomerized α-synuclein in these tumor xenografts led to a substantial upregulation of expression of major histocompatibility complex proteins in the melanoma cells, the latter of which is pertinent to enhancing anti-melanoma immune responses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240854 | GEO | 2024/05/21

REPOSITORIES: GEO

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Interfering with aggregated α-synuclein in advanced melanoma leads to a major upregulation of MHC class II proteins

Project description:Melanoma is the most serious and deadly form of skin cancer and with progression to advanced melanoma, the intrinsically disordered protein α-synuclein is upregulated to high levels; and while toxic to dopaminergic neurons in Parkinson’s disease, it is highly beneficial for primary and metastatic melanoma cells. To gain detailed insights, both at the level of the proteome and the transcriptome, into this exact opposite role of α-synuclein in advanced melanoma, we performed proteome and transcriptome studies of high-level α-synuclein-expressing primary and metastatic human melanoma cell lines and metastatic human melanoma xenografts treated with the small-molecule diphenyl-pyrazole compound anle138b, which binds to and interferes with the oligomeric structure of α-synuclein. Our data demonstrate that interfering with oligomerized α-synuclein in these melanoma cells and tumor xenografts leads to a substantial upregulation of major histocompatibility complex (MHC) proteins, which are important for enhancing anti-melanoma immune responses.

2024-07-03 | PXD030615 | Pride

System-based analyses of brain regions functionally impacted in Parkinson's disease reveals underlying causal mechanisms

Project description:Detailed analysis of disease-affected tissue provides insight into molecular mechanisms contributing to pathogenesis. Substantia nigra, striatum and cortex are functionally connected with increasing degrees of alpha-synuclein pathology in Parkinson's disease. Functional and causal pathway analysis of gene expression and proteomic alterations in these three regions revealed pathways that correlated with deposition of alpha-synuclein. Microarray and RNAseq experiments revealed previously unidentified causal changes related to oligodendrocyte function and synaptic vesicle release and other changes were reflected across all brain regions. Importantly a subset of these changes were replicated in Parkinson's disease blood. Proteomic assessment revealed alterations in mitochondria and vesicular transport proteins that preceded gene gene expression changes indicating defects in translation and/or protein turnover. Our combined approach of proteomics, RNAseq and microarray analyses provides a comprehensive view of the molecular changes that accompany alpha-synculein pathology in Parkinson's disease, and may be instrumental in understanding and diagnosing Parkinson's disease progression. Substantia Nigra (3 normal, 3 PD), Striatum (6 normal, 6 PD), Cortex (5 normal, 5 PD), Cortex non-PD neurodegeneration (2 normal, 3 DLB). Note Sample X201264 was used both for Cortex normal and for Cortex nonPD normal

2014-09-01 | E-GEOD-54282 | biostudies-arrayexpress

PDGFR-alpha inhibits melanoma growth via CXCL10/IP-10 and miR-503. A multi-omics approach.

Project description:Cutaneous melanoma is the most aggressive skin cancer showing high mortality at advanced clinical stages. Platelet-Derived Growth Factor Receptor alpha (PDGFR-alpha) is known to strongly inhibit melanoma and endothelial cells proliferation, in vitro as well in vivo. PDGFR-alpha expression has been found to be reduced in metastatic human melanoma-biopsies, as compared to benign nevi-biopsies, thus implying a negative selection of PDGFR-alpha expressing cells, in melanoma. In the present study PDGFR-alpha was transiently overexpressed in endothelial (HUVEC) and melanoma (SK-Mel-28) human cells; a strong anti-proliferation effect was observed, along with profound effects on mRNA and miRNA expression. In detail, gene-expression profiling showed that PDGFR-alpha over-expression affects the expression of 82 transcripts in HUVEC (41 up-, 41 down-regulated), and 52 Transcripts in SK-Mel-28 (43 up-, 9 down-regulated). Finally, a miRNA profiling showed that 14 miRs are up-regulated and 39 are down-regulated in PDGFR-alpha overexpressing cells. Accurate validation with alternative techniques demonstrated that CXCL10 is one of the most significantly up-regulated at both gene- and protein level, in combination with a strong down-regulation of miR-503 in both HUVEC and SK-Mel-28 overexpressing PDGFR-alpha. We then demonstrate that CXCL10 is a validated miR-503 target, and that the anti-proliferation effect of PDGFR-alpha is reverted by specific CXCL-10 neutralization. In conclusion, PDGFR-alpha overexpression strongly inhibits endothelial- and melanoma- proliferation in a CXCL-10 dependent way, by significantly down-regulating miR-503 expression. This data set contains the results of the mRNA analysis.

2016-11-14 | E-MTAB-4261 | biostudies-arrayexpress

PDGFR-alpha inhibits melanoma growth via CXCL10/IP-10 and miR-503. A multi-omics approach

Project description:Cutaneous melanoma is the most aggressive skin cancer showing high mortality at advanced clinical stages. Platelet-Derived Growth Factor Receptor alpha (PDGFR-alpha) is known to strongly inhibit melanoma and endothelial cell proliferation, in vitro as well in vivo. PDGFR-alpha expression has been found to be reduced in metastatic human melanoma-biopsies, as compared to benign nevi-biopsies, thus implying a negative selection of PDGFR-alpha expressing cells, in melanoma. In the present study PDGFR-alpha was transiently overexpressed in endothelial (HUVEC) and melanoma (SK-Mel-28) human cells; a strong anti-proliferation effect was observed, along with profound effects on mRNA and miR- expression. More in detail, gene-expression profiling showed that PDGFR-alpha over-expression affects the expression of 82 genes in HUVEC (41 up-, 41 down-regulated), and 52 genes in SK-Mel-28 (43 up-, 9 down-regulated). miRNA profiling showed that 14 miRs are up-regulated and 40 are down-regulated in PDGFR-alpha overexpressing cells. Accurate validation with alternative techniques demonstrated that CXCL10 gene expression is one of the most significantly up-regulated at both gene- and protein level, in combination with a strong down-regulation of miR-503 in both HUVEC and SK-Mel-28 overexpressing PDGFR-alpha. We then demonstrate that CXCL10 is a validated miR-503 target, and that the anti-proliferation effect of PDGFR-alpha is reverted by specific CXCL-10 neutralization. Several molecular pathways were identified in cells overexpressing PDGFR-alpha, according to KEGG and Gene Ontology analysis (p < 0.01). In conclusion, PDGFR-alpha overexpression strongly inhibits endothelial- and melanoma- proliferation in a CXCL-10 dependent way, by significantly down-regulating miR-503 expression. This dataset contains the results of the microRNA analysis.

2016-11-14 | E-MTAB-4266 | biostudies-arrayexpress

TNF-Î± as a key player in Melanoma cell aggressiveness

Project description:Purpose. Aggressiveness is a crucial issue related to cutaneous melanoma malignancy and its high metastatic potential. Aim of this work is to identify new pathways or molecules controlling melanoma cell aggressiveness. Proliferation, migration and invasion capability under serum stimulation were analyzed in 12 human metastatic melanoma cell lines to identify the most aggressive ones as a model. The most proliferating/invading (defines as the most aggressive) A375 cell line was compared to the less aggressive one, Sk mel 28 by means of different approaches: 1) transcriptomic analysis by ILLUMINA platform; 2) proteomic study through LC-MS/MS analysis; 3) multiplexed assay to measure secretion of cytokines in conditioned media bioinformatic analysis was then carried out. Two groups of cells significantly differing in aggressiveness were identified and 2 cell lines, namely A375 and SK-Mel-28 were selected as model of the most and the less aggressive phenotype, respectively. A multi-omic analysis of several experimental datasets derived from transcriptomic, proteomic (mass spectrometric) and cytokinomic data was then carried out via Ingenuity Pathway Analysis (IPA) software. Analysis of upstream regulators and network analysis, indicated that the expression of tumor necrosis factor (TNF) were significantly differently expressed and functioning. The involvement of these pathways was confirmed by functional validation studies as zymography and proliferation studies and the most significantly upregulated pathway (TNF-alfa) was tested. Five melanoma cell lines with different MAGS were treated with an anti-TNFÎ± monoclonal antibody and the most aggressive ones were highly significantly affected.

2019-01-08 | E-MTAB-4212 | biostudies-arrayexpress

Disseminated melanoma cells transdifferentiate into endothelial cells in intravascular niches at metastatic sites (Li et al. 2020, Cell Reports)

Project description:Here, we combined lineage tracing in a newly developed spontaneous metastatic mouse model of melanoma, advanced imaging and single-cell RNA-sequencing approaches to search for (patho) physiologically-relevant melanoma cellular states. We identified a population of reporter-positive melanoma cells located in intravascular niches of various metastatic organs. These intravascular metastatic cells were dormant, negative for characteristic melanoma markers and acquired endothelial cell markers.

2020-04-15 | GSE148666 | GEO

Comparative Proteomic Analysis Highlights Metabolic Dysfunction in α-synucleinopathy

Project description:The synaptic protein α-synuclein is linked through genetics and neuropathology to the pathogenesis of Parkinson’s disease and related disorders. However, the mechanisms by which α-synuclein influences disease onset and progression are incompletely understood. To identify novel pathways and potential therapeutic targets we performed proteomic analysis in a highly penetrant new Drosophila model of α-synucleinopathy. We identified 476 significantly upregulated and 563 significantly downregulated proteins in heads from α-synucleinopathy model flies compared to controls. We then used multiple complementary analyses to identify and prioritize genes and pathways within the large set of differentially expressed proteins for functional studies. We performed Gene Ontology enrichment analysis, integrated our proteomic changes with human Parkinson’s disease genetic studies, and compared the α-synucleinopathy proteome with that of tauopathy model flies, which are relevant to Alzheimer’s disease and related disorders. These approaches identified GTP cyclohydrolase (GCH1) and folate metabolism as candidate mediators of α-synuclein neurotoxicity. In functional validation studies we found that knockdown of Drosophila Gch1 enhanced locomotor deficits in α-synuclein transgenic flies, while folate supplementation protected from α-synuclein toxicity. Our integrative analysis suggested that mitochondrial dysfunction was a common downstream mediator of neurodegeneration. Accordingly, Gch1 knockdown enhanced metabolic dysfunction in α-synuclein transgenic fly brains while folate supplementation partially normalized whole brain bioenergetics. Here we outline and implement an integrative approach to identify and validate potential therapeutic pathways using comparative proteomics and genetics and capitalizing on the facile genetic and pharmacological tools available in Drosophila.

2021-09-09 | PXD021312 | Pride

Phenotypic manifestation of alpha-synuclein strains from Parkinson’s disease and multiple system atrophy in human dopaminergic neruons

Project description:Although α-synucleinis implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels of α-synuclein assemblies are toxic and how they cause progressive loss of human dopaminergic neurons. To address this issue, we used iPSC-derived dopaminergic neurons with a-synuclein triplication or controls where endogenous α-synuclein was imprinted into synthetic or disease-relevant conformations. We used α-synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) .We found that a 2.5-fold increase in α-synuclein levels in α-synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in α-synuclein gene expression.Transcriptomic analysis and isogenic correction of α-synuclein triplication revealed that intraneuronal α-synuclein levels solely and sufficiently explained vulnerability to cell death.

2020-09-02 | GSE149632 | GEO

Systems-based analyses of brain regions functionally impacted in Parkinson's disease reveals underlying causal mechanisms

2014-09-01 | GSE54282 | GEO

Expression data from oligodendroglial cell line

Project description:Coexpression of alpha-synuclein and p25alpha in an oligodendroglial cell line elicites a degenerative response that relies on aggregation and phosphorylation of alpha-synuclein at Ser129 We used microarray analysis to detail the changes in gene expression caused by alpha-synuclein aggregation followed by cellular degeneration Alpha-synuclein was coexpressed with p25alpha in an oligodendroglial cell line and mRNA was isolated at 8, 12, and 16 hrs after transfection. Gene expression was analyzed by two identical microarray set-ups

2013-10-28 | E-GEOD-51781 | biostudies-arrayexpress

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