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Genome-scale CRISPR screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma

ABSTRACT: Genome-scale CRISPR screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma

PROVIDER: PRJNA891211 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21860162_1.fastq.gz	Fastqsanger.gz
	SRR21860162_2.fastq.gz	Fastqsanger.gz
	SRR21860163_1.fastq.gz	Fastqsanger.gz
	SRR21860163_2.fastq.gz	Fastqsanger.gz
	SRR21860164_1.fastq.gz	Fastqsanger.gz

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Genome-scale CRISPR screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma [CRISPR sgRNA]

Project description:Genome-scale CRISPR screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma [CRISPR sgRNA]

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Genome-scale CRISPR screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma [RNA-seq]

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Genome-scale CRISPR screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma [RNA-seq]

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Genome-scale CRISPR screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma [CRISPR sgRNA]

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Genome-scale CRISPR screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma

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Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in triple-negative breast cancer

Project description:<p>Selective autophagy of mitochondria is known to promote survival and progression of cancer cells in various malignancies, including triple-negative breast cancer (TNBC). Here, we investigate the essential metabolic adaptations that support mitochondrial quality control in cancer cells with the aim to uncover therapeutically actionable metabolic vulnerabilities. Using TNBC as a model system and an integrated approach of proteomics and untargeted and stable-isotope resolved metabolomics, together with functional experimental analyses, we detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by an onco-metabolic program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle (EV)-mediated intracellular clearance of mitochondrial damage. Targeting of this sphingolipid pathway in cancer cells via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase (UGCG), resulted in ceramide-mediated compensatory mitophagy and subsequent cancer cell death in vitro and attenuated tumor growth and prolonged overall survival at clinically achievable doses in an orthotopic syngeneic mouse models of TNBC as well as in human cell-line derived xenograft models. Our study defines a mechanism of aberrant sphingolipid metabolism that underlies an actionable metabolic vulnerability for anti-cancer treatment.</p>

2025-09-30 | MTBLS13037 | MetaboLights

Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in triple-negative breast cancer

Project description:Selective autophagy of mitochondria is known to promote survival and progression of cancer cells in various malignancies, including triple-negative breast cancer (TNBC). Here, we investigate the essential metabolic adaptations that support mitochondrial quality control in cancer cells with the aim to uncover therapeutically actionable metabolic vulnerabilities. Using TNBC as a model system and an integrated approach of proteomics and untargeted and stable-isotope resolved metabolomics, together with functional experimental analyses, we detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by an onco-metabolic program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle (EV)-mediated intracellular clearance of mitochondrial damage. Targeting of this sphingolipid pathway in cancer cells via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase (UGCG), resulted in ceramide-mediated compensatory mitophagy and subsequent cancer cell death in vitro and attenuated tumor growth and prolonged overall survival at clinically achievable doses in an orthotopic syngeneic mouse models of TNBC as well as in human cell-line derived xenograft models. Our study defines a mechanism of aberrant sphingolipid metabolism that underlies an actionable metabolic vulnerability for anti-cancer treatment.

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Project description:Loss-of-function mutations in ARID1A define an aggressive subtype of diffuse gastric cancer (DGC) that is often resistant to standard chemotherapy. Here, we uncover a precise metabolic vulnerability in ARID1A-deficient DGC driven by a specific transporter defect. Through integrated metabolomic and transcriptomic analyses, we demonstrate that ARID1A loss transcriptionally represses the high-affinity nucleoside transporter SLC28A3. Our profiling revealed a critical lack of redundancy in the concentrative transporter family (CNT) in DGC, establishing a strict reliance on SLC28A3 for maintaining intracellular deoxycytidine (dC) pools. Consequently, ARID1A deficiency creates a severe "low-dCTP" metabolic bottleneck. We show that the dC analog Gemcitabine exploits this state through a distinct functional dichotomy: it enters via intact equilibrative transporters (ENTs) to target cells that have lost their competitive dC barrier. Mechanistically, Gemcitabine exerts a "dual-hit" effect by outcompeting the scarce dC pool for DNA incorporation while simultaneously inhibiting ribonucleotide reductase, thereby blocking de novo nucleotide synthesis. This synergistic collapse of pyrimidine metabolism was validated in patient-derived ex vivo cultures and in vivo peritoneal dissemination models. Our findings provide a robust mechanistic basis for repurposing Gemcitabine as a precision therapy for ARID1A-deficient DGC, offering a potent strategy for this intractable malignancy.

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