Metabolic analysis as a driver for discovery, diagnosis, and therapy

Cell, Journal Year: 2022, Volume and Issue: 185(15), P. 2678 - 2689

Published: July 1, 2022

Metabolic anomalies contribute to tissue dysfunction. Current metabolism research spans from organelles populations, and new technologies can accommodate investigation across these scales. Here, we review recent advancements in metabolic analysis, including small-scale metabolomics techniques amenable rare cell types, functional screening explore how cells respond stress, imaging approaches non-invasively assess perturbations diseases. We discuss provides an informative phenotypic dimension that complements genomic analysis Mendelian non-Mendelian disorders. also outline pressing challenges addressing them may further clarify the biochemical basis of human disease.

Language: Английский

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Protein synthesis, degradation, and energy metabolism in T cell immunity

Cellular and Molecular Immunology, Journal Year: 2022, Volume and Issue: 19(3), P. 303 - 315

Published: Jan. 4, 2022

T cell activation, proliferation, and differentiation into effector memory states involve massive remodeling of size molecular content create a increase in demand for energy amino acids. Protein synthesis is an energy- resource-demanding process; as such, changes production are intrinsically linked to proteome remodeling. In this review, we discuss how protein degradation change over the course immune response crosstalk between these processes metabolism. We highlight use high-resolution mass spectrometry analyze proteomes can improve our understanding regulated.

Language: Английский

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Emerging therapies in cancer metabolism

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(8), P. 1283 - 1303

Published: Aug. 1, 2023

Language: Английский

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Metabolism drives macrophage heterogeneity in the tumor microenvironment

Cell Reports, Journal Year: 2022, Volume and Issue: 39(1), P. 110609 - 110609

Published: April 1, 2022

Tumor-associated macrophages (TAMs) are a major cellular component in the tumor microenvironment (TME). However, relationship between phenotype and metabolic pattern of TAMs remains poorly understood. We performed single-cell transcriptome profiling on hepatic from mice bearing liver metastatic tumors. find that manifest high heterogeneity at levels transcription, development, metabolism, function. Integrative analyses validation experiments indicate increased purine metabolism is feature with pro-tumor terminal differentiation phenotypes. Like mouse TAMs, human highly heterogeneous. Human exhibit correlate poor therapeutic efficacy to immune checkpoint blockade. Altogether, our work demonstrates developmentally, metabolically, functionally heterogeneous may be key macrophage population.

Language: Английский

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Innate metabolic responses against viral infections

Nature Metabolism, Journal Year: 2022, Volume and Issue: 4(10), P. 1245 - 1259

Published: Oct. 20, 2022

Language: Английский

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Distinct metabolic states guide maturation of inflammatory and tolerogenic dendritic cells

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Sept. 2, 2022

Abstract Cellular metabolism underpins immune cell functionality, yet our understanding of metabolic influences in human dendritic biology and their ability to orchestrate responses is poorly developed. Here, we map single-cell states profiles inflammatory tolerogenic monocytic cells using recently developed multiparametric approaches. Single-cell pathway activation scores reveal simultaneous engagement multiple pathways distinct differentiation stages. GM-CSF/IL4-induce rapid reprogramming glycolytic monocytes transient co-activation mitochondrial followed by TLR4-dependent maturation cells. Skewing the mTOR:AMPK phosphorylation balance upregulation OXPHOS, fatty acid oxidation underpin hyperactivity an immunosuppressive phenotype cells, which exhibit maturation-resistance a de-differentiated marked unique immunoregulatory receptor signatures. This dataset provides important insights into impacting

Language: Английский

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Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(2), P. 314 - 330

Published: Jan. 30, 2023

The accumulation of acidic metabolic waste products within the tumor microenvironment inhibits effector functions tumor-infiltrating lymphocytes (TILs). However, it remains unclear how an environment affects T cell metabolism and differentiation. Here we show that prolonged exposure to acid reprograms intracellular mitochondrial fitness preserves stemness. Mechanistically, elevated extracellular acidosis impairs methionine uptake via downregulation SLC7A5, therefore altering H3K27me3 deposition at promoters key stemness genes. These changes promote maintenance a 'stem-like memory' state improve long-term in vivo persistence anti-tumor efficacy mice. Our findings not only reveal unexpected capacity maintain stem-like properties cells, but also advance our understanding

Language: Английский

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Tumor-associated macrophages restrict CD8+ T cell function through collagen deposition and metabolic reprogramming of the breast cancer microenvironment

Nature Cancer, Journal Year: 2024, Volume and Issue: 5(7), P. 1045 - 1062

Published: June 3, 2024

Language: Английский

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Tumor heterogeneity: preclinical models, emerging technologies, and future applications

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: April 28, 2023

Heterogeneity describes the differences among cancer cells within and between tumors. It refers to describing variations in morphology, transcriptional profiles, metabolism, metastatic potential. More recently, field has included characterization of tumor immune microenvironment depiction dynamics underlying cellular interactions promoting ecosystem evolution. been found most tumors representing one challenging behaviors ecosystems. As critical factors impairing long-term efficacy solid therapy, heterogeneity leads resistance, more aggressive metastasizing, recurrence. We review role main models emerging single-cell spatial genomic technologies our understanding heterogeneity, its contribution lethal outcomes, physiological challenges consider designing therapies. highlight how dynamically evolve because leverage this unleash recognition through immunotherapy. A multidisciplinary approach grounded novel bioinformatic computational tools will allow reaching integrated, multilayered knowledge required implement personalized, efficient therapies urgently for patients.

Language: Английский

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Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 2, 2023

Abstract Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. We here report on a human antigen-specific ex vivo model to explore new therapeutic options for cell immunotherapies. generated with this resemble tumor-infiltrating phenotypic and transcriptional level. Using targeted pooled CRISPR-Cas9 screen individual gene knockout validation experiments, we uncover sorting nexin-9 (SNX9) as mediator of exhaustion. Upon TCR/CD28 stimulation, deletion SNX9 in CD8 decreases PLCγ1, Ca 2+ , NFATc2-mediated signaling reduces expression NR4A1/3 TOX. enhances memory differentiation IFNγ secretion adoptively transferred results improved anti-tumor efficacy chimeric antigen receptor vivo. Our findings highlight that targeting is strategy prevent exhaustion enhance immunity.

Language: Английский

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