Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA211625 | ENA |
REPOSITORIES: ENA
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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: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.
2014-06-01 | GSE48782 | GEO
Project description:Melanoma incidence and mortality rates are historically higher for men than women. Although emerging studies have highlighted tumorigenic roles for the male sex hormone androgen and its receptor (AR) in melanoma, cellular and molecular mechanisms underlying these sex-associated discrepancies are poorly defined. Here, we delineate a previously undisclosed mechanism by which androgen-activated AR transcriptionally upregulates fucosyltransferase 4 (FUT4) expression, which drives melanoma invasiveness by interfering with adherens junctions (AJs). Global phosphoproteomic and fucoproteomic profiling, coupled with in vitro and in vivo functional validation, further reveals that AR-induced FUT4 fucosylates L1 cell adhesion molecule (L1CAM), which is required for FUT4-increased metastatic capacity. Tumor microarray and gene expression analyses demonstrate that AR-FUT4-L1CAM-AJs signaling correlates with pathological staging in melanoma patients. By delineating key androgen-triggered signaling that enhances metastatic aggressiveness, our findings help to explain sex-associated clinical outcome disparities and highlight AR/FUT4 and its effectors as potential prognostic biomarkers and therapeutic targets in melanoma.
2024-01-15 | PXD047335 | Pride
Project description:Melanoma incidence and mortality rates are historically higher for men than women. Although emerging studies have highlighted tumorigenic roles for the male sex hormone androgen and its receptor (AR) in melanoma, cellular and molecular mechanisms underlying these sex-associated discrepancies are poorly defined. Here, we delineate a previously undisclosed mechanism by which androgen-activated AR transcriptionally upregulates fucosyltransferase 4 (FUT4) expression, which drives melanoma invasiveness by interfering with adherens junctions (AJs). Global phosphoproteomic and fucoproteomic profiling, coupled with in vitro and in vivo functional validation, further reveals that AR-induced FUT4 fucosylates L1 cell adhesion molecule (L1CAM), which is required for FUT4-increased metastatic capacity. Tumor microarray and gene expression analyses demonstrate that AR-FUT4-L1CAM-AJs signaling correlates with pathological staging in melanoma patients. By delineating key androgen-triggered signaling that enhances metastatic aggressiveness, our findings help to explain sex-associated clinical outcome disparities and highlight AR/FUT4 and its effectors as potential prognostic biomarkers and therapeutic targets in melanoma.
2024-01-15 | PXD047337 | Pride
Project description:This project is an initiative to map the protein levels in malignant melanoma tumor samples, focused on in-depth histopathology coupled to proteome characterization. The protein levels and localization from this project were determined for a broad spectrum of diverse, surgically isolated melanoma tumors originating from multiple body locations. In this study, the quantitative mass-spectrometry-based proteomic analysis is interfaced with pathological tumor characterization, and associated with clinical data. All proteoforms and the generated data were identified by mass spectrometry and global proteomic experiments, from which chromosomal and sub-cellular localization was annotated within both primary and metastatic melanoma.
2021-07-16 | PXD026086 | Pride
Project description:Neuregulin (NRG) signaling through the receptor tyrosine kinase, ERBB3, is required for embryonic development, and dysregulated signaling has been associated with cancer progression. Here, we show that NRG1/ERBB3 signaling inhibits melanocyte (MC) maturation and promotes undifferentiated, migratory and proliferative cellular characteristics. Embryonic analyses demonstrated that initial MC specification and distribution were not dependent on ERBB3 signaling. However NRG1/ERBB3 signaling was both necessary and sufficient to inhibit differentiation of later stages of MC development in culture. Analysis of tissue arrays of human melanoma samples suggests that ERBB3 signaling may also contribute to metastatic progression of melanoma as ERBB3 was phosphorylated in primary tumors compared with nevi or metastatic lesions. Neuregulin 1-treated MCs demonstrated increased proliferation and invasion and altered morphology concomitant with decreased levels of differentiation genes, increased levels of proliferation genes and altered levels of melanoma progression and metastases genes. ERBB3 activation in primary melanomas suggests that NRG1/ERBB3 signaling may contribute to the progression of melanoma from benign nevi to malignancies. We propose that targeting ERBB3 activation and downstream genes identified in this study may provide novel therapeutic interventions for malignant melanoma. Gene expression changes are compared between Melan-Ink4a cells stimulated with NRG1-b1 (NRG1) for 21 days and NRG1 untreated Melan-INK4a cells in triplicate using Affymetrix Mouse GeneChip 1.0 ST chip .
2010-05-07 | E-GEOD-21463 | biostudies-arrayexpress
Project description:Activation of oncogenes often leads to induction of the DNA damage responses and onset of the cell senescence. Given that DNA damage can also trigger production of type I interferons (IFN) that contribute to senescence development, we sought to determine the role of IFN in the oncogene-induced senescence. Our data in mouse model demonstrate that inactivation of IFN signaling is sufficient for inducing melanomas in melanocytes harboring mutant Braf. Restoration of IFN signaling in IFN-deficient melanoma cells induces cell senescence and suppresses melanoma progression. In addition, data in human patients that received high dose IFN therapy and in mouse transplanted tumor models strongly suggest the importance of the non-cell-autonomous IFN signaling. Suppression of IFN signaling mediated by the downregulation of IFN receptor IFNAR1 invariably occurs during development of mouse melanoma. Mice harboring the IFNAR1 mutant, which is relatively resistant to downregulation, delay melanoma development, suppress the metastatic disease, and better respond to treatment with BRAF or PD1 inhibitors. These results suggest that IFN signaling is an important tumor suppressive pathway that inhibits melanoma development and progression. Accordingly, the inhibition of IFN pathway via IFNAR1 downregulation plays a key role in melanoma pathogenesis. Conversely, these data also argue for targeting IFNAR1 downregulation to prevent the metastatic disease and improve the efficacy of molecularly targeted and immune-targeted therapies. Two genotypes of mice were examined at 2 to 3 times after tamoxifen adminstration, with 2 replicates for each condition, yielding 8 samples in total.
2016-01-14 | E-GEOD-76842 | biostudies-arrayexpress
Project description:Tumor-derived exosomes are emerging as mediators of tumorigenesis with a tissue-specific address and message. We explored the function of melanoma-derived exosomes in formation of primary tumors and metastatic progression in both murine models and patients. Whereas exosomes from highly metastatic melanoma cells increased the metastatic behavior of primary tumor cells by educating bone marrow (BM) progenitor cells via the MET receptor, exosomes from low metastatic melanoma cells did not alter the incidence of metastases. Melanoma-derived exosomes induced vascular leakiness at pre-metastatic sites, and reprogrammed BM progenitor cells towards a pro-vasculogenic phenotype (c-Kit+Tie2+MET+). Reducing MET expression in tumor-derived exosomes diminished the pro-metastatic behavior of BM cells. Importantly, MET expression was upregulated in circulating BM progenitor cells (CD45-CD117low and CD45-CD117lowTIE2+) isolated from stage III and stage IV melanoma patients. Rab1a, Rab5b, Rab7, and Rab27a were highly expressed in melanoma and Rab27a RNA interference decreased exosome production and/or soluble angiogenic factors in melanoma cells, thereby preventing mobilization of BM progenitor cells, tumor growth and metastasis. Finally, we identified a melanoma signature in exosomes isolated from metastatic melanoma patients, comprised of TYRP2, VLA-4, Hsp70, an Hsp90 isoform and MET oncoprotein, which together with Rab proteins, appear to represent exosome-specific proteins with prognostic potential, and may provide new therapeutic targets. Identification of molecular finger associated to exosome effects in metastatic organs Microarray analysis of genes differentially expressed in the lungs 24 and 48 hours after B16-F10 exosome tail vein injection compared to control.
2012-05-26 | E-GEOD-36584 | biostudies-arrayexpress
Project description:Metabolomics dataset of serum from T3-treated dams. Related to following publication by Oelkrug et al: "Maternal thyroid hormone receptor beta activation sparks brown fat thermogenesis in the offspring"
2023-01-11 | MSV000091042 | GNPS