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

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

PROVIDER: PRJNA824311 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18672053.fastq.gz	Fastqsanger.gz
	SRR18672054.fastq.gz	Fastqsanger.gz
	SRR18672055.fastq.gz	Fastqsanger.gz
	SRR18672056.fastq.gz	Fastqsanger.gz
	SRR18672057.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]

2023-01-10 | GSE200358 | GEO

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.

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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]

| PRJNA824310 | ENA

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.

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

2023-01-10 | GSE200360 | GEO

Targeting Pyrimidine Synthesis Accentuates Molecular Therapy Response in Glioblastoma Stem Cells

Project description:Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo pyrimidine synthesis. Targeting the pyrimidine synthetic rate-limiting step enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamyolase, dihydroorotase) or the critical downstream enzyme, DHODH (dihydroorotate dehydrogenase) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through pyrimidine synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of pyrimidine synthesis and GSC tumorigenic capacity. Higher expression of pyrimidine synthesis genes portend poor prognosis of glioblastoma patients. Collectively, our results demonstrate a novel therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.

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RasV12 blocks DNA synthesis and DNA damage response

Project description:RasV12 blocks DNA synthesis and DNA damage response

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Targeting Pyrimidine Synthesis Accentuates Molecular Therapy Response in Glioblastoma Stem Cells

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