Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA285420 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2046002.fastq.gz | Fastqsanger.gz | |||
| SRR2046003.fastq.gz | Fastqsanger.gz | |||
| SRR2046004.fastq.gz | Fastqsanger.gz | |||
| SRR2046005.fastq.gz | Fastqsanger.gz |
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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
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.
2015-07-30 | GSE69403 | GEO
Project description:Metastatic melanoma is hallmarked by its ability to switch oncogenic MITF expression. Here we tested the impact of STAT3 on melanoma onset and progression in association with MITF expression levels. We established a mouse melanoma model for deleting Stat3 specifically in melanocytes with specific expression of human hyperactive NRASQ61K in an Ink4a deficient background. Mice with tissue specific Stat3 deletion showed an early onset of disease, but displayed significantly diminished lung metastasis. Whole genome expression profiling also revealed a reduced invasion phenotype, which was functionally confirmed in 3D melanoma model systems. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in up-regulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3 induced CEBPa/b expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that STAT3 enabled CEBPa/b binding to the MITF enhancer region thereby silencing it. We conclude that STAT3 is a metastasis driver able to antagonize the MITF oncogene via direct induction of CEBP family member transcription facilitating RAS-RAF-driven melanoma metastasis.
2021-09-01 | GSE119540 | GEO
Project description:Increased MITF expression contributes to melanoma progression and resistance to BRAF pathway inhibition. We show that, unexpectedly, lack of MITF is associated with more severe resistance to a range of inhibitors. Indeed, the presence of endogenous MITF was essential for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlated with expression of several activated receptor tyrosine kinases, most commonly AXL. The MITF-low/AXL-high/drug resistance phenotype was seen in roughly half of BRAF mutant and the majority of NRAS mutant melanoma cell lines. The dichotomous behavior of MITF in drug response was corroborated in vemurafenib-resistant biopsies, including MITF high and low clones in a relapsed patient. Drug cocktails containing AXL inhibitor enhanced melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas. Experssion analysis by RNAseq of 14 melanoma cell lines.
2014-09-19 | E-GEOD-61544 | biostudies-arrayexpress
Project description:Unlike MITF-M, the melanocyte-specific isoform of MITF, TFEB, TFE3 and non-melanocyte MITF isoforms are regulated primarily by mTORC1-mediated phosphorylation at the lysosome that promotes their cytoplasmic retention. As low levels of glucose or amino acids trigger down-regulation of MITF, it is likely that on nutrient limitation some MITF functions are assumed by TFE3 and TFEB, enabling MITFLow melanoma cells to survive and proliferate. The role TFEB and TFE3 in melanoma biology and their impact on MITF-driven proliferation is poorly understood.
2025-09-03 | GSE277250 | GEO
Project description:Unlike MITF-M, the melanocyte-specific isoform of MITF, TFEB, TFE3 and non-melanocyte MITF isoforms are regulated primarily by mTORC1-mediated phosphorylation at the lysosome that promotes their cytoplasmic retention. As low levels of glucose or amino acids trigger down-regulation of MITF, it is likely that on nutrient limitation some MITF functions are assumed by TFE3 and TFEB, enabling MITFLow melanoma cells to survive and proliferate. The role TFEB and TFE3 in melanoma biology and their impact on MITF-driven proliferation is poorly understood.
2025-09-03 | GSE270594 | GEO
Project description:Unlike MITF-M, the melanocyte-specific isoform of MITF, TFEB, TFE3 and non-melanocyte MITF isoforms are regulated primarily by mTORC1-mediated phosphorylation at the lysosome that promotes their cytoplasmic retention. As low levels of glucose or amino acids trigger down-regulation of MITF, it is likely that on nutrient limitation some MITF functions are assumed by TFE3 and TFEB, enabling MITFLow melanoma cells to survive and proliferate. The role TFEB and TFE3 in melanoma biology and their impact on MITF-driven proliferation is poorly understood.
2025-09-03 | GSE270590 | GEO
Project description:Unlike MITF-M, the melanocyte-specific isoform of MITF, TFEB, TFE3 and non-melanocyte MITF isoforms are regulated primarily by mTORC1-mediated phosphorylation at the lysosome that promotes their cytoplasmic retention. As low levels of glucose or amino acids trigger down-regulation of MITF, it is likely that on nutrient limitation some MITF functions are assumed by TFE3 and TFEB, enabling MITFLow melanoma cells to survive and proliferate. The role TFEB and TFE3 in melanoma biology and their impact on MITF-driven proliferation is poorly understood.
2025-09-03 | GSE270585 | GEO
Project description:Melanoma tumors are highly heterogeneous, comprising of different cell types that vary in their potential for growth and invasion. Heterogeneous expression of the Microphthalmia-associated Transcription Factor (MITF) and the POU domain transcription factor BRN2 (POU3F2) has been found in malignant melanoma. Changing expression of these transcription factors as the disease progresses has been linked to the metastatic mechanism of phenotype switching. We therefore investigated the effects of MITF and BRN2 expression in melanoma growth and metastasis. Depletion of MITF resulted in a cell population that had a slowed cell cycle progression, was less invasive in vitro and had hindered tumor and metastasis forming ability in mouse xenograft studies. BRN2 depletion left a cell population with intact proliferation and invasion in vitro; however metastatic growth was significantly reduced in the mouse xenograft model. These results suggest that the proliferative population within melanoma tumors express MITF, and both MITF and BRN2 are important for metastatic growth in vivo. This finding highlights the importance of BRN2 and MITF expression in development of melanoma metastasis.
2017-08-16 | GSE101434 | GEO
Project description:Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. Yet how metabolism is implicated in specific phenotypes, and whether lineage-restricted mechanisms control key metabolic vulnerabilities remains poorly understood. In melanoma, down-regulation of the lineage addiction oncogene Microphthalmia-associated Transcription Factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, though how MITF promotes proliferation and suppresses invasion is poorly defined. Here we show that MITF is a lineage restricted activator of the key lipogenic enzyme stearoyl-CoA desaturase (SCD), and that SCD is required for MITFHigh melanoma cell proliferation. By contrast MITFLow cells are insensitive to SCD inhibition. Significantly, the MITF-SCD axis suppresses metastasis, inflammatory signalling, and an ATF4-mediated feedback-loop that maintains dedifferentiation. Our results reveal that MITF is a lineagespecific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype-switching, and highlight that cell phenotype dictates response to drugs targeting lipid metabolism.
2019-10-16 | GSE137390 | GEO