Broad-Spectrum Therapeutic Suppression of Metastatic Melanoma Through Nuclear Hormone Receptor Activation
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE48782 | GEO | 2014/06/01
SECONDARY ACCESSION(S): PRJNA211625
REPOSITORIES: GEO
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Project description:Melanoma metastasis is a devastating outcome in need of novel preventive therapies. We provide pharmacologic, nolecuar, and genetic evidence establishing the liver-X nuclear hormone receptor (LXR) as a therapeutic target in melanoma. Molecular and genetic experiments revealed these effects to be mediated by LXRb, which elicits these outcomes through transcriptional induction of tumoral and systemic apolipoprotein-E (ApoE). LXRb agonism robustly suppressed tumor growth and metastasis across a wide spectrum of melanoma lines of diverse mutational subtypes established in xenograft, immunocompetent, and genetically-initiated model. We propose a path for the clinical testing of LXRb targeting-a therapeutic approach that uniquely acts by transcriptionally acivating a metastasis suppressor gene. In this experiment we analyzed the effect of GW3965 treatment on gene expression in the MeWo human melanoma cell line. The cells were treated either with DMSO or GW3965 at 1 micromolar for 48 hours, after which the RNA was extracted and gene expression was analyzed by transcriptomic profiling
2014-06-01 | E-GEOD-48782 | biostudies-arrayexpress
Project description:The nuclear receptors LXRa and LXRb play a crucial role in regulating hepatic lipid metabolism. Many genes induced in response to pharmacologic LXR agonism in mouse liver have been defined; however, the transcriptional consequences of loss of LXR binding to its genomic targets are not well characterized. Here we addressed how deletion of both LXRa and LXRb from mouse liver (LXRDKO) affects the transcriptional regulatory landscape by integrating changes in LXR/RXR binding, chromatin accessibility, and gene expression. Many genes involved in fatty acid metabolism have reduced expression and chromatin accessibility at their intergenic and intronic regions in LXRDKO livers. Genes that were upregulated in LXRDKO livers have increased chromatin accessibility in their promoter regions and are enriched for those with functions not linked to lipid metabolism. We further showed that loss of LXR binding in liver reduces the activity of a broad set of hepatic transcription factors, inferred through motif accessibility. In contrast, accessibility at promoter NFY motifs is strongly increased in the absence of LXR. Surprisingly, we define small set of direct target genes for ligand-dependent LXR repression. These genes with LXR binding sites show increased expression in LXRDKO liver and reduced expression in response to LXR agonist treatment. In summary, while our results support the established roles for LXRs as ligand-dependent activators of genes linked to lipid metabolism, the binding of LXR/RXR heterodimers to the hepatic genome has broad effects on the transcriptional landscape that extend beyond its canonical function as an activator of lipid metabolic genes.
2022-01-25 | GSE191030 | GEO
Project description:LXRs (LXRa and LXRb) are widely expresded in a variety of cell types. We addressed how transient LXR activation using GW3965 impacts the cellular composition and/or transcriptional changes in the SI of WT mice.
2024-07-19 | GSE227726 | GEO
Project description:Liver X receptors (LXRs) are important regulators of cholesterol, lipid and glucose metabolism and have been extensively studied in liver, macrophages and adipose tissue. However, their role in skeletal muscle is not yet fully elucidated and the functional role of each of the LXRM-NM-1 and LXRM-NM-2 subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRM-NM-1 and LXRM-NM-2 knockout (KO) mice were established. The present study shows that treatment with the unselective LXR agonist T0901317 increased mRNA levels of LXR target genes such as sterol regulatory element-binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1) and ATP-binding cassette transporter A1 (ABCA1) in myotubes established from WT and LXRM-NM-1 KO mice. However, only minor changes in expression level were observed for these genes after treatment with T0901317 in myotubes from LXRM-NM-2 KO mice. Gene expression analysis using Affymetrix NuGO Genechip arrays showed that few other genes than the classical, well known LXR target genes were regulated by LXR in skeletal muscle. Furthermore, functional studies using radiolabeled substrates showed that treatment with T0901317 increased lipogenesis and apoA1 dependent cholesterol efflux, in myotubes from WT and LXRM-NM-1 KO mice, but not LXRM-NM-2 KO mice. The data suggest that the lipogenic effects of LXRs, as well as the LXR-stimulated cholesterol efflux, are mainly mediated by LXRM-NM-2 in skeletal muscle. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRa and LXRb knockout (KO) mice were established. Sixteen samples were examined. Half the samples were treated with the unselective LXR agonist T0901317.
2010-03-30 | E-GEOD-13192 | biostudies-arrayexpress
Project description:We established a model of human melanoma metastasis to identify differentially expressed genes in brain metastasis, compared to cutaneous melanoma from which they were developed. Such genes may control brain metastasis. The identification and characterization of these genes would advance the understanding of the metastatic process and may lead to new diagnostics and therapeutic approach. Brain metastases occur in almost 40% of melanoma patients. The median survival of such patients does not exceed a few months. Very little information is available on mechanisms underlying the progression of melanoma towards brain metastasis. The function, and significance of the various factors involved in melanoma progression must be deciphered using relevant models. Currently, most human melanoma brain metastasis models consist of xenografted cells inoculated into immune-deficient mice mainly by intracarotid or intra-cardiac administration. We generated a reproducible melanoma brain metastasis model, consisting of brain-metastasizing variants and local, sub-dermal variants that originate from the same melanomas thus sharing a common genetic background. The brain metastasizing variants were obtained by intra-cardiac inoculation. One of the brain metastasizing variants when inoculated sub-dermally yielded spontaneous brain dormant micrometastasis. Cells from the spontaneous brain micrometastasis when removed from the brain microenvironment proliferate very well in vitro and generate tumors in the skin being the orthotopic organ site. The brain metastasis and micro-metastasis cells expressed higher levels of ANGPTL4, COX-2, MMP1, MMP2 and PRAME and lower levels of CLDN1, CYR61 and IL-6R than the cutaneous variants. These gene products may be involved in melanoma brain metastasis and may serve as novel brain metastasis biomarkers and targets for therapy. 8 Samples (arrays) were analyzed. We generated pairwise comparisons between cutaneous and brain metastatic variants of the same genetic background, using Partek Genomics Suite, in the three melanoma models. Genes with pM-bM-^IM-$5% and a fold-change difference of M-bM-^IM-%1.25 or <-1.25 were selected.
2011-03-17 | E-GEOD-27980 | biostudies-arrayexpress
Project description:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematological. We used transcriptomic analysis to investigate LXR pathway, and cholesterol metabolism in leukemic cells. Malignancy with a poor prognosis that derives from plasmacytoid dendritic cells (PDC). No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared to those of acute myeloid leukemia (AML) and T-acute lymphoblastic leukemia (T-ALL), as well as the transcriptomic signature of primary PDC. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of ATP Binding Cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with three signaling pathways associated with leukemic cell survival, namely: NF-κB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor IL-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with an increased survival after LXR agonist treatment. This demonstrates that cholesterol homeostasis is modified in BPDCN and can be normalized by treatment with LXR agonists which can be proposed as a new therapeutic approach.
2017-02-10 | GSE89565 | GEO
Project description:Liver X receptors (LXRα and LXRβ) are nuclear receptor transcription factors that play crucial roles in regulating metabolic and immune functions in macrophages. Both receptors are present in macrophages and exhibit significant sequence similarity, yet their specific roles in various macrophage models, especially in inflammatory contexts, remain underexplored. Prior research has demonstrated that ligand-activated LXRs can suppress the expression of pro-inflammatory cytokines in macrophages. Here, we explored the genomic landscape of LXRa under inflammatory conditions using BMDM lacking LXRb as previously described (de la Rosa et al 2024); we treated BMDM with synthetic LXR ligand GW3965 alone or in combination with lipopolysaccharide for 24h.
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