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Lineage-restricted regulation of SCD and fatty acid saturation by MITF controls melanoma phenotypic plasticity

ABSTRACT: Lineage-restricted regulation of SCD and fatty acid saturation by MITF controls melanoma phenotypic plasticity

PROVIDER: PRJNA565365 | ENA |

REPOSITORIES: ENA

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Lineage-restricted regulation of SCD and fatty acid saturation by MITF controls melanoma phenotypic plasticity

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

Regulation of SCD and fatty acid saturation by MITF controls melanoma phenotypic plasticity

Project description:The ability of cancer cells to switch phenotype in response to a dynamic intra-tumor microenvironment is a major barrier to effective therapy. In melanoma, down-regulation of the lineage addiction oncogene MITF (Microphthalmia-associated transcription factor) is a hallmark of the proliferative-to-invasive phenotype switch. Yet how MITF promotes proliferation and suppresses invasion is poorly understood. Here we show that expression of the key lipogenic enzyme stearoyl-CoA desaturase (SCD) is activated by MITF, but suppressed by the stress-responsive transcription factor ATF4. SCD expression is required for MITF-positive melanoma cell proliferation,. By contrast, MITF-low cells express reduced levels of SCD and are insensitive to its inhibition, indicating that cell phenotype dictates response to drugs targeting lipid metabolism. Since SCD suppresses inflammatory signalling and ATF4 expression, the results identify a positive feedback-loop that can maintain an invasive phenotype, uncover a key role for MITF and ATF4 in metabolic reprograming, and reveal fatty acid composition as a driver of melanoma phenotype-switching.

2019-11-19 | PXD010254 | Pride

MITF regulates SCD and fatty acid saturation to control melanoma phenotypic state.

Project description:MITF regulates SCD and fatty acid saturation to control melanoma phenotypic state.

| PRJNA565361 | ENA

Lineage-Restricted Regulation of SCD and Fatty Acid Saturation by MITF Controls Melanoma Phenotypic Plasticity.

Project description: Not available

| S-EPMC7137507 | biostudies-literature

MITF regulates SCD and fatty acid saturation to control melanoma phenotypic state.

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-10-16 | GSE137392 | GEO

Transcriptome shifts triggered by vitamin A and SCD genotype interaction in Duroc pigs

Project description:Background The composition of intramuscular fat depends on genetic and environmental factors, including the diet. In pigs, we identified a haplotype of three SNP mutations in the steaoryl-coA desaturase (SCD) gene promoter associated with higher content of monounsaturated fatty acids in intramuscular fat. The second of these three SNPs (rs80912566, C>T) affected a putative retinol response element in the SCD promoter. The effect of dietary vitamin A restriction over intramuscular fat content is controversial in pigs as it seems to depend on the genetic line and the duration of the restriction. This study aims to investigate changes in the muscle transcriptome in SCD rs80912566_TT and CC pigs fed with and without vitamin A supplement during the fattening period. Results Vitamin A did not affect carcass fattening traits and fatty acid composition in muscle, but we observed an interaction between vitamin A and SCD genotype on the desaturation of muscle fatty acids. The diet without vitamin A supplement tended to enlarge the compositional differences between genotypes. The interaction between diet and genotype was also evident at the transcriptome level, the highest number of differentially expressed genes were detected between SCD rs80912566_TT pigs fed with the two diets. Conclusions Restricting dietary vitamin A during the fattening period did not improve intramuscular fat content despite relevant changes in muscle gene expression, both in coding and non-coding genes. Despite this, there was a significant interaction between the SCD genotype and the dietary vitamin A, which affected the quality of the meat through a change in the saturation index of intramuscular fat and activated general pathways of retinol response in a SCD genotype-dependant manner.

2021-09-12 | GSE183909 | GEO

NHLBI TOPMed: Outcome Modifying Gene in SCD (OMG-SCD)

Project description:NHLBI TOPMed: Outcome Modifying Gene in SCD (OMG-SCD)

| PRJNA472122 | ENA

NHLBI TOPMed: Outcome Modifying Gene in SCD (OMG-SCD)

Project description:NHLBI TOPMed: Outcome Modifying Gene in SCD (OMG-SCD)

| PRJNA472123 | ENA

Opaque filamentation in Low Phosphate (LP) and Sorbitol (SOR) compared to in SCD

Project description:Act1-Wor1 strain (the opaque strain CAY2903 with constitute WOR1 expression), wildtype white (a/a RBY717); Opaque hyphal formation in liquid LP and SOR compared to SCD; white cells in the same conditions as control. 6 condition experiment: opaque and white cells in LP, SOR and SCD. Used the pool of all conditions as reference.

2013-04-01 | E-GEOD-42963 | biostudies-arrayexpress

MITF-low zebrafish melanomas reveal cells with no MITF activity at the site of residual disease

Project description:The MITF-low melanoma transcriptional signature is predictive of poor outcome for patients but little is known about its biological signature. We used genetic models of zebrafish with low expression of mitfa (MITF-low) to study this biological subtype. We performed whole bulk RNA-seq to classify zebrafish MITF-low melanoma that cluster mainly by their directionality of growth and assess their resemblance to patients’ MITF-low subgroups. Furthermore, using genetic inhibition of MITF activity we discover minimal residual disease at the site of regression and using single-cell and low input RNA-seq we characterise these MITF independent cells and show that they pre-exist in the primary tumour.

2019-10-09 | GSE130037 | GEO

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