Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

GABA regulates electrical activity and tumor initiation in melanoma

ABSTRACT: Oncogenes can only initiate tumors in certain cellular contexts, which is referred to as oncogenic competence. In melanoma, whether cells in the microenvironment can endow such competence remains unclear. Using a combination of zebrafish transgenesis coupled with human tissues, we demonstrate that GABAergic signaling between keratinocytes and melanocytes promotes melanoma initiation by BRAFV600E. GABA is synthesized in melanoma cells, which then acts on GABA-A receptors on keratinocytes. Electron microscopy demonstrates specialized cell-cell junctions between keratinocytes and melanoma cells, and multi-electrode array analysis shows that GABA acts to inhibit electrical activity in melanoma/keratinocyte co-cultures. Genetic and pharmacologic perturbation of GABA synthesis abrogates melanoma initiation in vivo. These data suggest that GABAergic signaling across the skin microenvironment regulates the ability of oncogenes to initiate melanoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236806 | GEO | 2023/07/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Interactions of melanoma cells with distal keratinocytes trigger metastasis via Notch signaling inhibition of MITF

Project description:The most critical stage in initiation of melanoma metastasis is the radial to vertical growth transition, yet the triggers of this transition remain elusive. We introduce a novel perspective, suggesting that the microenvironment drives melanoma metastasis independently of mutation acquisition. Here we examined the changes in microenvironment that occur during melanoma radial growth. We show that direct contact of melanoma cells with the remote epidermal layer triggers vertical invasion via Notch signaling activation, the latter serving to inhibit MITF function. Briefly, within the native Notch ligand-free microenvironment, MITF, the melanocyte lineage master regulator, binds and represses miR-222/221 promoter in an RBPJK-dependent manner. However, when radial growth brings melanoma cells into contact with distal differentiated keratinocytes that express Notch ligands, the activated Notch intracellular domain impairs MITF binding to miR-222/221 promoter. This de-repression of miR-222/221 expression triggers initiation of invasion. Our findings may direct novel prevention opportunities via targeting specific microenvironment. Two replicates of Notch-activated cells that were seeded on Delta-like-1 (DLL1) (2 ng/µl ) coated plates were compared to two replicates of cells without Notch activation. The goal of this experiment is to evaluate the changes of miRs expression in melanoma cells upon Notch signaling activation.

2015-07-30 | E-GEOD-69403 | biostudies-arrayexpress

Interactions of melanoma cells with distal keratinocytes trigger metastasis via Notch signaling inhibition of MITF

2015-07-30 | GSE69403 | GEO

Melanoma cells repress Desmoglein 1 in keratinocytes to promote tumor cell migration

Project description:Melanoma is an aggressive cancer typically arising from transformation of melanocytes residing in the basal layer of the epidermis, where they are in direct contact with surrounding keratinocytes. The role of keratinocytes in shaping the melanoma tumor microenvironment remains understudied. We previously showed that temporary loss of the keratinocyte-specific cadherin, Desmoglein 1 (Dsg1) controls paracrine signaling between normal melanocytes and keratinocytes to stimulate the protective tanning response. Here, we provide evidence that melanoma cells hijack this intercellular communication by secreting factors that keep Dsg1 expression low in surrounding keratinocytes, which in turn generate their own paracrine signals that enhance melanoma spread through CXCL1/CXCR2 signaling. Evidence suggests a model whereby paracrine signaling from melanoma cells increases levels of the transcriptional repressor Slug, and consequently decreases expression of the Dsg1 transcriptional activator Grhl1. Together, these data support the idea that paracrine crosstalk between melanoma cells and keratinocytes resulting in chronic keratinocyte Dsg1 reduction contributes to melanoma cell movement associated with tumor progression.

2023-09-11 | GSE239634 | GEO

Developmental chromatin programs determine oncogenic competence in melanoma [ATAC-seq]

Project description:Oncogenes are only transforming in certain cellular contexts, a phenomenon called oncogenic competence. Here, using a combination of a human pluripotent stem cell-derived cancer model along with zebrafish transgenesis, we demonstrate that the transforming ability of BRAFV600E along with additional mutations depends upon the intrinsic transcriptional program present in the cell of origin. In both systems, melanocytes are largely resistant to mutations, whereas both neural crest and melanoblast populations are readily transformed. Profiling reveals that progenitors have higher expression of chromatin modifying enzymes such as ATAD2, a melanoma competence factor that forms a complex with SOX10 and allows for expression of downstream oncogenic and neural crest programs. These data suggest that oncogenic competence is mediated by regulation of developmental chromatin factors, which then allow for proper response to those oncogenes.

2021-04-15 | GSE172028 | GEO

Rapid conversion of fibroblasts into functional forebrain GABAergic interneurons by direct genetic reprogramming

Project description:Transplantation of GABAergic interneurons (INs) can sustain long-standing benefits in animal models of epilepsy and other neurological disorders. In a therapeutic perspective, a renewable source of functional GABAergic INs is needed. Here, we identified five factors (Foxg1, Sox2, Ascl1, Dlx5 and Lhx6) able to convert fibroblasts directly into induced GABAergic INs (iGABA-INs), displaying the molecular signature of telencephalic INs. The selected factors recapitulate in fibroblasts the activation of transcriptional networks required for the specification of GABAergic fate during telencephalon development. iGABA-INs exhibited progressively maturing firing patterns comparable to those of cortical INs, had synaptic currents and released GABA. Importantly, upon grafting in the hippocampus, iGABA-INs survived, matured and their optogenetic stimulation triggered GABAergic transmission and inhibited the activity of connected granule cells. The five factors also converted human cells into functional GABAergic neurons. These properties define iGABA-INs as a promising tool for disease modeling and cell-based therapeutic approaches. Comparison of iGABA-INs transcriptional profile with those of starting fibroblasts and GAD67-GFP+ cortical interneurons.

2015-12-15 | E-GEOD-74065 | biostudies-arrayexpress

p53 amyloid induced cellular transformation and tumor formation in the mouse xenograft model

Project description:p53 amyloid formation is predicted to be involved in cancer initiation, but the direct evidence of how altered p53 acts as an oncogene is lacking. Cells with p53 amyloids show enhanced survival, apoptotic resistance with increased proliferation and migration rates. Proteomic profiling of cells containing p53 aggregates suggests that p53 amyloid formation triggers aberrant expression of pro-oncogenes while downregulating the tumor-suppressive genes. We propose that wild-type p53 amyloid formation can potentially contribute to the initiation of tumor development.

2022-07-16 | PXD019498 | Pride

High-plex spatial RNA profiling reveals cell type-specific biomarker expression during melanoma development

Project description:Early diagnosis of melanoma is critical for improved survival. However, biomarkers of early melanoma evolution and their origin within the tumor and its microenvironment, including the keratinocytes, are poorly defined. To address this, we used spatial transcript profiling that maintains the morphological tumor context to measure expression of >1,000 RNAs in situ in patient-derived formalin-fixed, paraffin-embedded tissue sections in primary melanoma and melanocytic nevi. We profiled 134 200µm-diameter regions of interest enriched in melanocytes, neighboring keratinocytes or immune cells. This approach captured distinct expression patterns across cell types and tumor types during melanoma development. Unexpectedly, we discovered that S100A8 is expressed by keratinocytes within the tumor microenvironment during melanoma growth. Immunohistochemistry of 252 tumors showed prominent keratinocyte-derived S100A8 expression in melanoma but not in benign tumors and confirmed the same pattern for S100A8’s binding partner S100A9, suggesting that injury to the epidermis may be an early and easily detectable indicator of melanoma development Together, our results establish a framework for high-plex, spatial and cell type-specific resolution of gene expression in archival tissue applicable to the development of biomarkers and characterization of tumor-microenvironment interactions in tumor evolution. In this dataset, we capture the GeoMx DSP RNA profiling data associated with this study. The files here represent patients with melanocytic tumors (n = 16) which were profiled with the NanoString GeoMx pilot panel (n=4 patients, n=108 gene targets) or CTA developmental panel v1.0 (n=12 patients, n=1,412 gene targets). These panels were read out using Illumina sequencing according to manufacturer protocols. For access to high resolution (single channel, composite, or ROI) images please contact mkriner@nanostring.com.

2021-03-03 | GSE168013 | GEO

Fibroblasts potentiate melanoma cells in vitro invasivity induced by UV-irradiated keratinocytes - transcription profiling

Project description:Melanoma represents a malignant disease with steadily increasing incidence. Despite a remarkable enrichment of therapeutic repertoire achieved in the last decade, primarily limited sensitivity to therapy or acquired resistance are common. These phenomena limit survival of patients in advanced stages of the disease. UV-irradiation is a very important factor in melanoma initiation. In this study, we tested the influence of normal dermal fibroblasts as well as cancer-associated fibroblasts isolated from melanoma on UV-irradiated keratinocytes as an inductor of melanoma cell migration in 3-D collagen gels. The introduction of normal dermal fibroblasts and mainly cancer-associated fibroblasts to such system further significantly stimulated melanoma cells invasivity. A panel of candidate gene products responsible for facilitation of melanoma cells invasion was defined with emphasis on IL6, IL8 and CXCL1.

2018-01-10 | E-MTAB-5973 | biostudies-arrayexpress

Nrg1/ErbB4 signaling contributes to the effects of the ketogenic diet on GABAergic activity and seizures

Project description:The ketogenic diet (KD) has been used as an effective therapy to treat epilepsy. Previous studies indicate an elevated level of GABA in the brain by KD treatment. However, the underlying mechanisms remain to be elucidated. Here we report that KD treatment suppresses seizures in both acute and chronic seizure models and enhances presynaptic GABA release probability in the hippocampus. By screening molecular targets that potentially linked to GABAergic activity with transcriptome analysis, we identify that KD treatment dramatically increased the Nrg1 gene expression in the hippocampus. Disruption of Nrg1 signaling by genetically deleting its receptor-ErbB4 or blocking ErbB4 kinase activity abolishes KD’s effects on GABAergic activity and seizures. Mechanistically, KD treatment increases Nrg1 expression via up-regulating histone acetylation. Our findings suggest a critical role of Nrg1/ErbB4 signaling in mediating KD’s effects on GABAergic activity and seizures, which sheds light on the development of new therapeutic interventions to seizure control.

2020-08-24 | GSE156687 | GEO

Smoking-mediated Up-regulation of GAD67 Expression in the Human Airway Epithelium

Project description:Gamma-aminobutyric acid (GABA) is a multifunctional mediator that functions as a neurotransmitter in the central nervous system and a trophic factor during nervous system development, affecting proliferation, differentiation and cell death [1-3].GABA is synthesized from glutamate, catalyzed by GAD65 and GAD67, glutamic acid decarboxylase {Tillakaratne, Medina-Kauwe, et al. 1995 21 /id}{Owens & Kriegstein 2002 3 /id}{Watanabe, Maemura, et al. 2002 73 /id}. In the CNS transporters and catabolic enzymes work in a coordinated fashion to control the availability of GABA {Tillakaratne, Medina-Kauwe, et al. 1995 21 /id}{Owens & Kriegstein 2002 3 /id}{Watanabe, Maemura, et al. 2002 73 /id} It is now recognized that GABA also functions in a variety of organs outside of the CNS [1,3,4]. In the lung, a series of recent studies suggest that the GABAergic signaling system plays a role in the control of asthma related-airway constriction and mucin secretion [5-9]. In the context that goblet cell hyperplasia and mucin overproduction is associated with cigarette smoking [10-12], we hypothesized that components of the GABAergic system may also be altered in the airway epithelium of cigarette smokers. To assess this hypothesis, we evaluated the expression of the entire GABAergic system in the large and small airway epithelium of healthy nonsmokers and healthy smokers. The data demonstrates there is expression of genes for a complete GABAergic system in the airway epithelium. Interestingly, the expression of GAD67 was markedly modified by smoking, with increased expression in healthy smokers compared to healthy nonsmokers at the mRNA and protein levels. In the context that mucus overproduction is commonly associated with cigarette smoking, GAD67 may be a pharmacologic target for treatment of smoking-related disorders.

2017-02-09 | GSE17905 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data