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

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

PROVIDER: PRJNA824308 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18686008.fastq.gz	Fastqsanger.gz
	SRR18686009.fastq.gz	Fastqsanger.gz
	SRR18686010.fastq.gz	Fastqsanger.gz
	SRR18686011.fastq.gz	Fastqsanger.gz
	SRR18686012.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.

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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 [SCRB-seq]

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

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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.

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

2023-01-10 | GSE200360 | GEO

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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Metabolic Dependency on De Novo Pyrimidine Synthesis in Platinum Resistant Ovarian Cancer

Project description:Recurrent high grade serous ovarian cancer (OC) is mostly lethal due to development of resistance to platinum-based chemotherapy. We used cisplatin resistant (Cis-R) cells generated by repeat cisplatin treatment of sensitive (Cis-S) OC cell lines, and metabolomics to identify critical factors associated with platinum resistance. Pathway analysis of differentially abundant metabolites in Cis-R vs. Cis-S OVCAR5 and COV362 cells identified enrichment of pyrimidine metabolism (FDR<0.05) produced by increased de novo pyrimidine synthesis which was subsequently confirmed by flux analysis. Inhibition of this pathway using the DHODH inhibitor brequinar (BRQ) decreased viability, and produced expression changes in genes of the mitochondrial electron transport in Cis-R compared with Cis-S cells. Oxygen consumption rate (OCR) measured with a Seahorse assay indicated lower (P<0.05) OCR (baseline, ATP-related, and maximal) and spare respiratory capacity (SRC) in Cis-R vs. Cis-S OVCAR5 cells. In addition, BRQ had dose-related inhibitory effects on OCR across assay conditions in both Cis-R and Cis-S cells, SRC however, was inhibited by BRQ only in Cis-R cells. In vivo, BRQ attenuated growth of intraperitoneal (ip) Cis-R tumor xenografts but did not alter Cis-S tumors. Similarly, tumor growth was inhibited (p<0.01) by BRQ in a Cis-R PDX model. BRQ plus carboplatin enhanced (p<0.05) the inhibitory effects of carboplatin alone on total tumor weight and numbers of Cis-R ip tumor xenografts. Results indicate that Cis-R cells develop mechanisms that enhance de novo pyrimidine synthesis and maintain relatively low levels of mitochondrial oxidation, however these changes make Cis-R cells vulnerable to inhibitors of these processes.

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