Lactylation fuels nucleotide biosynthesis and facilitates deuterium metabolic imaging of tumor proliferation in H3K27M-mutant gliomas

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

ABSTRACT Oncogenes hyperactive lactate production, but the mechanisms by which facilitates tumor growth are unclear. Here, we demonstrate that is essential for nucleotide biosynthesis in pediatric diffuse midline gliomas (DMGs). The oncogenic histone H3K27M mutation upregulates phosphoglycerate kinase 1 (PGK1) and drives production from [U- 13 C]-glucose DMGs. Lactate activates nucleoside diphosphate NME1 via lactylation promotes synthesis of triphosphates proliferation. Importantly, show this mechanistic link between glycolysis provides a unique opportunity deuterium metabolic imaging Spatially mapping 2 H-lactate [6,6- H]-glucose allows visualization metabolically active lesion an early readout response to standard-of-care radiation targeted therapy precedes extended survival reflects pharmacodynamic alterations at tissue level preclinical DMG models vivo clinical field strength (3T). In essence, have identified H3K27M-lactate-NME1 axis proliferation non-invasive STATEMENT OF SIGNIFICANCE This study establishes role driving glucose using DMI clinically relevant models. Our studies lay foundation precision patients.

Language: Английский

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The adaptor protein Miro1 modulates horizontal transfer of mitochondria in mouse melanoma models

Cell Reports, Journal Year: 2025, Volume and Issue: 44(1), P. 115154 - 115154

Published: Jan. 1, 2025

Recent research has shown that mtDNA-deficient cancer cells (ρ0 cells) acquire mitochondria from tumor stromal to restore respiration, facilitating formation. We investigated the role of Miro1, an adaptor protein involved in movement along microtubules, this phenomenon. Inducible Miro1 knockout (Miro1KO) mice markedly delayed formation after grafting ρ0 cells. Miro1KO with fluorescently labeled revealed delay was due hindered mitochondrial transfer grafted B16 cells, which impeded recovery respiration and growth. led perinuclear accumulation impaired mobility network. In vitro experiments decreased association compromising via tunneling nanotubes (TNTs) mesenchymal Here we show horizontal mouse melanoma models vivo its involvement TNTs.

Language: Английский

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Comprehensive Integrated Analysis Reveals the Spatiotemporal Microevolution of Cancer Cells in Patients with Bone-Metastatic Prostate Cancer

Biomedicines, Journal Year: 2025, Volume and Issue: 13(4), P. 909 - 909

Published: April 9, 2025

Background/Objectives: Bone metastasis is a frequent and life-threatening event in advanced cancers, affecting up to 70–85% of prostate cancer patients. Understanding the cellular molecular mechanisms underlying bone essential for developing targeted therapies. This study aimed systematically characterize heterogeneity microenvironmental adaptation metastases using single-cell transcriptomics. Methods: We integrated largest transcriptome dataset date, encompassing 124 samples from primary tumors, various metastatic sites, non-malignant tissues (e.g., benign prostatic hyperplasia, normal marrow). After quality control, 602,497 high-quality transcriptomes were analyzed. employed unsupervised clustering, gene expression profiling, mutation analysis, metabolic pathway reconstruction cell subtypes tumor remodeling. Results: Cancer epithelial cells dominated microenvironment but exhibited pronounced heterogeneity, posing challenges conventional clustering methods. By integrating genetic features, we revealed key evolutionary trajectories during metastasis. Notably, identified novel subpopulation, NEndoCs, characterized by unique differentiation patterns distinct spatial distribution across niches. also observed significant reprogramming recurrent mutations linked prostate-to-bone transitions. Conclusions: comprehensively elucidates patterns, reprogramming, cancer, providing targets clinical strategies precise treatment cancer.

Language: Английский

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Ivosidenib Confers BRCAness Phenotype and Synthetic Lethality to Poly (ADP-Ribose) Polymerase Inhibition in BRCA1/2-Proficient Cancer Cells

Biomedicines, Journal Year: 2025, Volume and Issue: 13(4), P. 958 - 958

Published: April 14, 2025

Background/Objectives: PARP inhibitors (PARPi) are pivotal to treating homologous recombination repair-deficient (HRD) cancers, particularly BRCA1/2-mutated ovarian and breast cancers. However, most cancers harbor wild-type (WT) BRCA1/2, limiting PARPi eligibility. This study aims identify an approved drug that could induce a BRCAness phenotype, thereby sensitizing WT BRCA PARPi. Methods: Ovarian cancer cell lines with BRCA1/2 were treated ivosidenib. HR repair efficiency was assessed via RAD51 foci formation reporter assays. Synthetic lethality evaluated using viability colony Mechanistic studies included RNA-binding protein pulldown, co-immunoprecipitation, functional analyses of DNA pathways. YTHDC2′s role in investigated through siRNA knockdown rescue experiments. Results: Ivosidenib significantly reduced sensitized cells PARPi, inducing synthetic lethality. Mechanistically, ivosidenib directly bound YTHDC2, m6A reader critical for HR. interaction disrupted ability promote double-strand break HR, evidenced by impaired recruitment proteins (e.g., BRCA1, RAD51) accumulation damage (γH2AX foci). YTHDC2 phenocopied effects, while overexpression rescued defects. Conclusions: induces targeting suppressing enhancing sensitivity. uncovers novel, metabolism-independent mechanism ivosidenib, repositioning it as therapeutic agent HRD tumors. These findings propose strategy expand eligibility addressing unmet need oncology.

Language: Английский

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Emerging Biomarkers in Metabolomics: Advancements in Precision Health and Disease Diagnosis

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(23), P. 13190 - 13190

Published: Dec. 8, 2024

Metabolomics has come to the fore as an efficient tool in search for biomarkers that are critical precision health approaches and improved diagnostics. This review will outline recent advances biomarker discovery based on metabolomics, focusing metabolomics reported cancer, neurodegenerative disorders, cardiovascular diseases, metabolic health. In provides evidence unique oncometabolites important early disease detection monitoring of treatment responses. Metabolite profiling conditions such mental disorders can offer diagnosis mechanisms into especially Alzheimer's Parkinson's diseases. addition these, lipid other metabolites relating promising patient stratification personalized treatment. The gut microbiome environmental exposure also feature among influential factors because they sculpt individual profiles, impacting overall Further, we discuss technological current clinical applications, challenges faced by validation toward medicine. Finally, this discusses future opportunities regarding integration routine healthcare enable preventive approaches.

Language: Английский

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