Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance
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ABSTRACT:
PROVIDER: PRJNA648045 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12301900_1.fastq.gz | Fastqsanger.gz | |||
| SRR12301900_2.fastq.gz | Fastqsanger.gz | |||
| SRR12301901_1.fastq.gz | Fastqsanger.gz | |||
| SRR12301901_2.fastq.gz | Fastqsanger.gz | |||
| SRR12301902_1.fastq.gz | Fastqsanger.gz |
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Project description:Ever-increasing understanding about the complexity of factors and regulatory layers that contribute to immune evasion facilitates the development of immunotherapies. However, the diversity of malignant tumors limits many known mechanisms in specific genetic and epigenetic contexts, manifesting the need to discover general driver genes. Here, we have identified the m6A demethylase FTO as an essential epitranscriptomic regulator utilized by tumors to escape immune surveillance through regulation of glycolytic metabolism. We show that FTO-mediated m6A demethylation in tumor cells elevates transcription factors c-Jun, JunB, and C/EBPβ, which allows the rewiring of glycolytic metabolism. Fto knockdown impairs the glycolytic activity of tumor cells, which restores the function of CD8+ T cells, thereby inhibiting tumor growth. Furthermore, we developed a small-molecule compound Dac51 that can inhibit the activity of FTO, block FTO-mediated immune evasion, and synergize with checkpoint blockade for better tumor control, suggesting reprogramming RNA epitranscriptome as a potential strategy for immunotherapy.
2021-04-30 | GSE154952 | GEO
Project description:Despite immune checkpoint blockades have achieved remarkable success, most patients with solid tumors do not respond or develop resistance, suggesting additional treatment strategies are needed. Concentrated efforts are directed toward revitalizing the IFNγ pathway or amplifying antigen presentation capabilities, alternative mechanisms underlying immune evasion remain poorly understood. Using an unbiased whole-genome in vivo natural selection screen, we identified an uncharacterized role of Monoacylglycerol O-Acyltransferase 1 (Mogat1) as a critical modulator of tumor immune evasion. As tumors progress and expand, they undergo systemic metabolic adaptations to evade immune surveillance. Tumor cells exploit Mogat1 to sequester excess fatty acids into triglycerides, orchestrating metabolic reprogramming that simultaneously fuels tumor growth and creates an immunosuppressive microenvironment. Mogat1 inhibition suppresses tumor growth by promoting T-cell infiltration and cytotoxicity. Remarkably, Mogat1 loss facilitates the circumvention of PD-1 checkpoint blockade resistance. This heightened inflammatory response, characterized by increased interferon sensitivity, circumvents the need for conventional antigen presentation. Our findings reveal a novel lipid metabolism-centered mechanism of immune evasion and offer a potential strategy to enhance cancer immunotherapy efficacy.
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Project description:Quiescent tissue stem cells evade immune surveillance
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Project description:Mogat1 drives metabolic adaptations to evade immune surveillance
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Project description:Single nucleotide polymorphisms in intron 1 of the fat mass and obesity-associated (FTO) gene were found to be associated with an increased risk of adult obesity. Enhanced FTO expression in mice leads to hyperphagia, increased fat mass, and higher body weight. Neuronal-specific FTOâ??deleted mice have an identical lean body weight phenotype to global FTO-deleted mice. The physiological role of adipose FTO in the homeostasis of energy regulation remains to be elucidated. We used microarrays to elucidate the metabolic pathways that are regulated by FTO in the white fat. FTO flox/flox and Adiponectin-cre FTO flox/flox (AFO) mice were fed with chow diet. White fat tissues from epididymal adipose pad were harvested under ad lib condition for RNA isolation. Three independent pools of FTO flox/flox and AFO mouse white fat RNA were included in the study.
2016-07-03 | E-GEOD-65098 | biostudies-arrayexpress
Project description:Stem cells are critical for the maintenance of many tissues, and thus their integrity is crucial, but whether this integrity is maintained in the face of an immune response is not well defined. Here we set out to determine the outcome of T cell interactions with adult stem cells in their physiological niche. We find that fast cycling epithelial stem cells, including Lgr5+ intestinal stem cells, as well as ovary and mammary stem cells, are eliminated by activated T-cells, but slow cycling stem cells, specifically hair follicle and muscle stem cells, are resistant to T-cell killing. This is an intrinsic property of the quiescent stem cells resulting from systemic downregulation of the antigen presentation machinery, including MHC class I, Tap proteins, and the transactivator Nlrc5, which is reversed upon stem cell entry into the cell cycle. These findings identify a link between tissue stem cell quiescence, antigen presentation, and immune evasion, and may help explain why mutations in long-lived stem cells would not lead to immune editing. They also suggest how cancer-initiating cells may evade immune surveillance
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Project description:Here we use MeRIP-Seq to analyze global adenosine methylation (m6A) in mRNAs in the midbrain and striatum of Fto-deficient mice. We find that Fto deficiency leads to increased methylation within a subset of mRNAs important for neuronal signaling, including many within the dopaminergic signaling pathway. Collectively, our results show that Fto regulates demethylation of specific mRNAs in vivo, and this activity relates to control of dopaminergic transmission. Profiling of m6A in midbrain and striatum from FTO knockout mice
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Project description:In this study, we aimed to examine the changes in gene expression that occur in FTO over expressing mice in order to gain more insight into the underlying mechanisms by which FTO influences body weight and adiposity
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Project description:To gain insight into FTO function, we knocked down and overexpressed FTO in HEK293 cells.Genetrail analyses of expression profiles pointed to the RNA splicing and processing machinery. Intriguingly, using immunocytochemistry and confocal laser scanning microscopy, we observed strong enrichment of FTO in nuclear speckles and - to a lesser extent - in nucleoli, but not in other known nuclear bodies. We also studied RNA samples of Fto knockout and wild type mice with regard to content of methylated and unmethylated nucleosidesand observed that ratios of modified and unmodified uracil and adenine were different depending on the presence of FTO. Taken together, our data suggest that FTO is involved in RNA processing and modification. We used microarrays to investigate global gene expression changes depending on the level of FTO We compared FTO overexpressing and FTO depleted cells to cells with endogeneus level of FTO to determine global gene expression changes.
2012-11-13 | E-GEOD-33870 | biostudies-arrayexpress
Project description:We identified the target genes of FTO ("fat mass and obesity associated") in primary cultures of human skeletal muscle cells using adenoviral vectors expressing FTO or GFP and oligonucleotide microarrays. Human myotubes were prepared from 4 different skeletal muscle biopsies. After differentiation, myotubes were infected for 48 hours with recombinant adenovirus expressing either GFP or FTO. Each FTO-infected myotubes culture was compared to GFP-infected myotubes culture. GFP-infected myotubes were regarded as the control. Four biological replicates were processed.
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