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Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [SCRB-seq]

ABSTRACT: Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [SCRB-seq]

PROVIDER: PRJNA824310 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18672347_1.fastq.gz	Fastqsanger.gz
	SRR18672347_2.fastq.gz	Fastqsanger.gz
	SRR18672348_1.fastq.gz	Fastqsanger.gz
	SRR18672348_2.fastq.gz	Fastqsanger.gz
	SRR18672349_1.fastq.gz	Fastqsanger.gz

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Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [SCRB-seq]

Project description:Blocking pyrimidine de novo synthesis via inhibiting Dihydroorotate dehydrogenase (DHODH) is clinically used to treat autoimmunity and to prevent the growth of rapidly dividing cells including activated T-cells. We identified a previously unrecognized resistance of precursors of memory T-cells to pyrimidine starvation. While the treatment effectively blocks effector T-cells, numbers, function and transcriptional profiles of memory T-cells and their precursors remain completely unaltered. We pinpoint this effect to a narrow time-window in the early T-cell expansion phase, when developing effector, but not memory T-cells are selectively vulnerable to pyrimidine starvation. This stems from a higher proliferative pace of early effector T-cells paired with lower pyrimidine synthesis capacity compared to memory precursors. This differential sensitivity constitutes a novel, drug-targetable checkpoint that efficiently diminishes effector T-cells without harming the memory compartment. We envision that knowledge of this pyrimidine synthesis-based cell fate-determining particularity opens up new means to safely manipulate effector T-cell responses.

2023-01-10 | GSE200359 | GEO

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [bulk RNA-seq]

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Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [scRNA-Seq 10x]

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Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development.

Project description:Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development.

| PRJNA824308 | ENA

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [bulk RNA-seq]

Project description:Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [bulk RNA-seq]

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Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [scRNA-Seq 10x]

Project description:Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [scRNA-Seq 10x]

| PRJNA824806 | ENA

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development.

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

2023-01-10 | GSE200360 | GEO

PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth

Project description:Aerobic glycolysis, which is also termed the Warburg effect, is one of the aberrant metabolic pathways in highly proliferating cells. Glycolysis provides glycolytic metabolites to support the generation of biomass, such as nucleotides, amino acids, and lipids. To date, no studies have explored interrelationships between glycolysis and other metabolic pathways. Phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) activates glycolysis by synthesizing fructose-2,6-bisphosphate (F2,6BP), which allosterically activates the rate-limiting enzyme 6-phosphofructo-1-kinase (PFK-1). In this study, we found that PFKFB3 directly interacts with and regulates the phosphorylation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), the enzyme catalyzing the first three steps of de novo pyrimidine synthesis. PFKFB3 inactivation reduced de novo pyrimidine synthesis, RNA and DNA production, and the growth of cancer and proliferative cells. Thus, the glycolytic activator PFKFB3 bridges glycolysis with pyrimidine synthesis, unites both glucose metabolism and nucleic acid metabolism, and contributes to cell proliferation under both physiological and pathological conditions.

2025-06-16 | PXD048755 | Pride

De Novo Pyrimidine Synthesis Is a Collateral Metabolic Vulnerability in NF2-deficient Mesothelioma

Project description:Pleural mesothelioma (PM) is one of the deadliest cancers, with limited therapeutic options due to its therapeutically intractable genome, which is characterized by the functional inactivation of tumor suppressor genes (TSGs) and high tumor heterogeneity, including diverse metabolic adaptations. However, the molecular mechanisms underlying these metabolic alterations remain poorly understood, particularly how TSG inactivation rewires tumor metabolism to drive tumorigenesis and create metabolic dependencies. Through integrated multi-omics analysis, we identify for the first time that NF2 loss of function defines a distinct PM subtype characterized by enhanced de novo pyrimidine synthesis, which NF2-deficient PM cells are critically dependent on for sustained proliferation in vitro and in vivo. Mechanistically, NF2 loss activates YAP, a downstream proto-oncogenic transcriptional coactivator in the Hippo signalling pathway, which in turn upregulates CAD and DHODH, key enzymes in the de novo pyrimidine biosynthesis pathway. Our findings provide novel insights into metabolic reprogramming in PM, revealing de novo pyrimidine synthesis as a synthetic lethal vulnerability in NF2-deficient tumors. This work highlights a potential therapeutic strategy for targeting NF2-deficient mesothelioma through metabolic intervention.

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De Novo Pyrimidine Synthesis Is a Collateral Metabolic Vulnerability in NF2-deficient Mesothelioma

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