Ontology highlight
ABSTRACT:
PROVIDER: PRJNA989594 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25098466_1.fastq.gz | Fastqsanger.gz | |||
| SRR25098466_2.fastq.gz | Fastqsanger.gz | |||
| SRR25098467_1.fastq.gz | Fastqsanger.gz | |||
| SRR25098467_2.fastq.gz | Fastqsanger.gz | |||
| SRR25098468_1.fastq.gz | Fastqsanger.gz |
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Project description:Tumor cells must rewire nucleotide synthesis to satisfy the demands of unbridled proliferation. Meanwhile, they exhibit augmented reactive oxygen species (ROS) production which paradoxically damages DNA and free dNTPs. How these metabolic processes are integrated to fuel tumorigenesis remains to be investigated. MYC family oncoproteins are central regulators that coordinate nucleotide synthesis and ROS generation to drive the development of numerous human cancers. We herein performed a CRISPR-based functional screen targeting metabolic genes and identified nudix hydrolase 1 (NUDT1) as a MYC-driven metabolic dependency. Mechanistically, MYC orchestrated the balance of two metabolic pathways that act in parallel, the NOX4-ROS pathway and the PLK1-NUDT1 nucleotide-sanitizing pathway. We describe LC-1-40 as the first-in-class degrader that potently and selectively depletes NUDT1 in vivo. Administration of LC-1-40 disrupted MYC-controlled metabolic homeostasis, resulting in excessive nucleotide oxidation, cytotoxicity and therapeutic responses in patient-derived xenografts. Thus, pharmacological targeting of NUDT1 represents an actionable MYC-driven metabolic liability.
2023-12-27 | PXD043444 | Pride
Project description:Multiple myeloma is an incurable hematological malignancy evolving from precursor states to advanced phases of the disease. MYC abnormalities play a critical role in the disease progression. Nevertheless, MYC lacks therapeutic drugability, thereby necessitating the exploration of alternative strategies aimed at circumventing the challenges associated with targeting MYC. In this study, we hypothesized that MYC upregulation induces genomic dependencies in tumor cells, creating vulnerabilities that can be exploited therapeutically. We discovered a differential dependency on glutamine metabolism in MYC overexpressing cells. We functionally explored these dependencies as a selective targetable vulnerability in vitro and in vivo. Furthermore, we uncovered a potential synergistic combination that can exacerbated this metabolic vulnerability, Collectively, our in vitro and in vivo results revealed an effective therapeutic combinatory strategy in the context of MYC overexpressing MM.
2024-04-09 | PXD050010 | Pride
Project description:Multiple myeloma is an incurable hematological malignancy evolving from precursor states to advanced phases of the disease. MYC abnormalities play a critical role in the disease progression. Nevertheless, MYC lacks therapeutic drugability, thereby necessitating the exploration of alternative strategies aimed at circumventing the challenges associated with targeting MYC. In this study, we hypothesized that MYC upregulation induces genomic dependencies in tumor cells, creating vulnerabilities that can be exploited therapeutically. We discovered a differential dependency on glutamine metabolism in MYC overexpressing cells. We functionally explored these dependencies as a selective targetable vulnerability in vitro and in vivo. Furthermore, we uncovered a potential synergistic combinations that can exacerbated this metabolic vulnerability, Collectively, our in vitro and in vivo results revealed an effective therapeutic combinatory strategy in the context of MYC overexpressing MM.
2023-09-04 | GSE241948 | GEO
Project description:MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor characterized by therapy resistance and disease recurrence. Here we integrated data from unbiased genetic screening and metabolomic profiling to identify multiple cancer-selective metabolic vulnerabilities in MYC-driven MB tumor cells, which are amenable to therapeutic targeting. Among these targets, dihydroorotate dehydrogenase (DHODH), an enzyme that catalyzes de novo pyrimidine biosynthesis, emerged as a favorable candidate for therapeutic targeting. Mechanistically, DHODH inhibition acts on-target leading to uridine metabolite scarcity and hyperlipidemia, accompanied by reduced protein O-GlcNAcylation and c-Myc degradation. Pyrimidine starvation evokes a metabolic stress response that leads to cell cycle arrest and apoptosis. We further show that an orally available small molecule DHODH inhibitor demonstrates potent mono-therapeutic efficacy against patient-derived MB xenografts in vivo. The reprogramming of pyrimidine metabolism in MYC-driven medulloblastoma represents an unappreciated therapeutic strategy and a potential new class of treatments with stronger cancer selectivity and fewer neurotoxic sequelae.
2022-11-09 | GSE214956 | GEO
Project description:MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor characterized by therapy resistance and disease recurrence. Here we integrated data from unbiased genetic screening and metabolomic profiling to identify multiple cancer-selective metabolic vulnerabilities in MYC-driven MB tumor cells, which are amenable to therapeutic targeting. Among these targets, dihydroorotate dehydrogenase (DHODH), an enzyme that catalyzes de novo pyrimidine biosynthesis, emerged as a favorable candidate for therapeutic targeting. Mechanistically, DHODH inhibition acts on-target leading to uridine metabolite scarcity and hyperlipidemia, accompanied by reduced protein O-GlcNAcylation and c-Myc degradation. Pyrimidine starvation evokes a metabolic stress response that leads to cell cycle arrest and apoptosis. We further show that an orally available small molecule DHODH inhibitor demonstrates potent mono-therapeutic efficacy against patient-derived MB xenografts in vivo. The reprogramming of pyrimidine metabolism in MYC-driven medulloblastoma represents an unappreciated therapeutic strategy and a potential new class of treatments with stronger cancer selectivity and fewer neurotoxic sequelae.
2022-11-09 | GSE214802 | GEO
Project description:MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor characterized by therapy resistance and disease recurrence. Here we integrated data from unbiased genetic screening and metabolomic profiling to identify multiple cancer-selective metabolic vulnerabilities in MYC-driven MB tumor cells, which are amenable to therapeutic targeting. Among these targets, dihydroorotate dehydrogenase (DHODH), an enzyme that catalyzes de novo pyrimidine biosynthesis, emerged as a favorable candidate for therapeutic targeting. Mechanistically, DHODH inhibition acts on-target leading to uridine metabolite scarcity and hyperlipidemia, accompanied by reduced protein O-GlcNAcylation and c-Myc degradation. Pyrimidine starvation evokes a metabolic stress response that leads to cell cycle arrest and apoptosis. We further show that an orally available small molecule DHODH inhibitor demonstrates potent mono-therapeutic efficacy against patient-derived MB xenografts in vivo. The reprogramming of pyrimidine metabolism in MYC-driven medulloblastoma represents an unappreciated therapeutic strategy and a potential new class of treatments with stronger cancer selectivity and fewer neurotoxic sequelae.
2022-11-09 | GSE214801 | GEO
Project description:Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related death worldwide and has been increasing in recent years in developed nations1,2. The MYC oncogene or its paralogs are frequently amplified or overexpressed in particularly aggressive subtypes of cancer associated with stem cell-like features and worse clinical outcomes3,4, including in liver cancer5. Unfortunately, selective inhibitors that target MYC or its transcriptional program are not yet clinically available for therapy of HCC. Here, we identified methionine metabolism as a selective vulnerability for MYC but not RAS-driven liver cancers. MYC-driven liver cancer cells are methionine dependent and S-adenosylmethionine (SAM), the predominant methyl donor, partially rescues methionine depletion. A low methionine diet, or the methylation inhibitor 5-azacytidine limited MYC-driven tumor formation, but RAS-driven liver cancer was resistant to a low methionine diet. Metabolic tracing of methionine catabolism in MYC high cells identified increased m5C methylation of genomic DNA or ribosomal RNA. We identified NOP2, an rRNA m5C-methyltransferase as a MYC target gene. Knockdown of NOP2 selectively inhibited MYC liver cancer cell proliferation and in vivo tumorigenesis. Thus, methionine catabolism is critical for MYC-driven liver tumorigenesis and NOP2 may serve as a new therapeutic target in liver cancer.
2022-10-06 | GSE214724 | GEO
Project description:The c-MYC oncogene is a key transcription factor deregulated in most human tumors. Histone marks associated with transcriptionally active genes in euchromatic islands define the set of high-affinity c-MYC targets. The mechanisms involved in their recognition by c-MYC are not known but likely involve chromatin-remodelling and chromatin-modifying complexes. Here, we show that c-MYC interacts with BPTF, a core subunit of the NURF complex that binds active chromatin. BPTF is required for the activation of the full c-MYC transcriptional programme in fibroblasts. BPTF knockdown leads to a decrease in c-MYC recruitment to DNA and to changes in chromatin accessibility. Using BPTF-null MEFs we show that BPTF is necessary for c-MYC-driven proliferation, G1-S progression, and replication stress, but not for c-MYC-driven apoptosis. Consistently, BPTF is required for the proliferation of cells driven by c-MYC, such as Burkitt lymphoma, and its expression in human cancer lines correlates with the activation of c-MYC gene signatures. Our findings point to the c-MYC-BPTF axis as a potential therapeutic target in cancer. To assess whether BPTF is required for the transcriptional activity of c-MYC, human foreskin fibroblasts (HFF) were stably transduced with the chimeric MYC-ER cDNA (HFF MYC-ER) and infected with lentiviruses coding for either control (shNt) or BPTF-targeting shRNAs. Cells were serum-starved for 2 days to achieve quiescence and then treated with 4-hydroxytamoxifen (4-OHT)
2016-01-19 | E-GEOD-65544 | biostudies-arrayexpress
Project description:Arabidopsis nudix hydrolase 7 knock-out mutant Atnudt7-1 exhibits a reduced size phenotype when compared with age-matched Col-0 wildtype plants growing in potting mix of 12 parts vermiculite: 3 parts redi-earth and 1 part sand. In these array experiments the differences in gene expression caused by this mutation is assessed in comparison to wildtype plants.
2010-08-31 | E-MEXP-2711 | biostudies-arrayexpress