Targeting Pyrimidine Synthesis Accentuates Molecular Therapy Response in Glioblastoma Stem Cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA531324 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8863352.fastq.gz | Fastqsanger.gz | |||
| SRR8863353.fastq.gz | Fastqsanger.gz | |||
| SRR8863354.fastq.gz | Fastqsanger.gz | |||
| SRR8863355.fastq.gz | Fastqsanger.gz |
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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.
2019-04-09 | GSE129438 | GEO
Project description:Nucleotides are essential building blocks for nucleic acid synthesis, signaling, and metabolism. Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited target for cancer therapy. However, resistance frequently emerges, highlighting the need for a deeper understanding of nucleotide regulation. Here, we use uridine-sensitized CRISPR-Cas9 screening to reveal novel regulators of pyrimidine synthesis. We identify NUDT5 which we show binds to and negatively regulates PPAT, the rate-limiting enzyme in purine biosynthesis. We demonstrate the NUDT5-PPAT interaction prevents excessive purine production, maintains phosphoribosyl pyrophosphate (PRPP), a critical substrate for pyrimidine synthesis, and thus enhances conversion of nucleobase analogs into active anti-cancer molecules. We further report that NUDT5 regulates PPAT independently of its enzymatic activity and can be displaced by PRPP, revealing intricate allosteric regulation. Our findings reveal a previously unrecognized mechanism for maintaining nucleotide balance and positions NUDT5 as a potential therapeutic target for overcoming resistance to chemotherapy in proliferative diseases.
2025-10-29 | PXD060320 | Pride
Project description:Nucleotides are essential building blocks for nucleic acid synthesis, signaling, and metabolism. Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited target for cancer therapy. However, resistance frequently emerges, highlighting the need for a deeper understanding of nucleotide regulation. Here, we use uridine-sensitized CRISPR-Cas9 screening to reveal novel regulators of pyrimidine synthesis. We identify NUDT5 which we show binds to and negatively regulates PPAT, the rate-limiting enzyme in purine biosynthesis. We demonstrate the NUDT5-PPAT interaction prevents excessive purine production, maintains phosphoribosyl pyrophosphate (PRPP), a critical substrate for pyrimidine synthesis, and thus enhances conversion of nucleobase analogs into active anti-cancer molecules. We further report that NUDT5 regulates PPAT independently of its enzymatic activity and can be displaced by PRPP, revealing intricate allosteric regulation. Our findings reveal a previously unrecognized mechanism for maintaining nucleotide balance and positions NUDT5 as a potential therapeutic target for overcoming resistance to chemotherapy in proliferative diseases.
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Project description:Macrophage-mediated phagocytosis plays a pivotal role in eradicating cancer cells and modulating anti-tumor immunity. Yet, the mechanisms through which cancer cells evade phagocytosis remain elusive. We employed a genome-wide CRISPR screen in murine pancreatic cancer cells co-cultured with macrophages and discovered that disabling the tumor-intrinsic pyrimidine synthesis pathway (specifically Cad, Dhodh, and Umps) leads to enhanced phagocytosis by macrophages. Mechanistically, macrophages suppress the UMP salvage pathway in tumor cells, increasing their dependence on de novo UMP synthesis. This suppression resulted in tumor cells with impaired de novo pyrimidine synthesis becoming more susceptible to apoptosis in the presence of macrophages, thereby enhancing macrophage-mediated elimination, both in vitro and in mouse models. Mechanistically, we show that pro-inflammatory cytokines released by macrophages, including TNFα and IL-1, are essential for upregulating Upp1 and decrease UMP pool in tumor cells. Thus, our findings uncover how tumor pyrimidine metabolism pathway shape their sensitivity to macrophage-mediated elimination.
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Project description:Targeting plasticity in the pyrimidine synthesis pathway potentiates macrophage-mediated phagocytosis in pancreatic cancer models
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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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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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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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