Metabolomics-LC-MS

Metabolomics (LC-MS / NMR)

一行要約

Metabolomics は LC-MS / GC-MS / NMR で組織・細胞・血漿中の小分子代謝産物 (50-1500 Da) を網羅的に定量し、代謝表現型と機能をリンクさせる omics 手法。腫瘍領域では Warburg, glutamine addiction, lipid metabolism (脳転移), tryptophan-IDO/AhR 軸, immunometabolism (citraconate / itaconate / lactate / kynurenine が IO 応答性 / 好中球機能 / T 細胞 exhaustion を規定) の研究で中心的役割。Cachexia, EV 内代謝産物 cargo, brain met fatty acid β-oxidation 等の領域に応用。

原理

(1) 試料採取・抽出: 組織 → 急速凍結 → polar / non-polar 二相抽出 (methanol-chloroform-water, MTBE 法)。(2) 分離・検出: LC-MS (HILIC for polar, C18 for lipid), GC-MS (volatile / derivatized), NMR (¹H で broad coverage)。high-resolution MS (Orbitrap) で accurate mass、Q-TOF で fragmentation。(3) データ解析: MS-DIAL / XCMS / MetaboAnalyst で peak picking → annotation (HMDB, METLIN, MoNA で MS² match) → normalization → multivariate (PCA / PLS-DA) → pathway analysis (MetaboAnalyst pathway, Reactome metabolite mapping)。(4) ¹³C / ¹⁵N isotope tracing: pulse-chase 標識基質で metabolic flux を定量 (SIRM / 13C-MFA)。

主要エビデンス / 適用領域

• Immunometabolism: citraconate / itaconate (IRG1) が IFN-γ, T-cell exhaustion を制御 (Science-2026-Li et al. 等); IDO/TDO → kynurenine → AhR が Treg / MDSC 誘導
• Lactate と TME: 高 lactate が CD8 T 細胞機能抑制, MCT1/4 阻害剤研究
• Glutamine addiction: KEAP1 mut NSCLC で glutaminolysis 依存性、CB-839 (telaglenastat) 治療研究
• Brain metastasis lipid metabolism: brain met が fatty acid β-oxidation / cholesterol metabolism に依存
• Cachexia: 血漿 / 筋肉 metabolite signature で early detection / 介入対象
• EV cargo metabolite: tumor EV 中の metabolite が distant niche を rewire
• Neutrophil metabolism: TAN の glycolysis vs OXPHOS shift, NETosis の metabolic basis

適用分野と限界

• 強み: phenotype に直結する終末層、isotope tracing で flux 同定可能、blood / urine / CSF biomarker 直接適用
• 限界: annotation が依然 incomplete (50-70% of peaks unannotated)、isomer 区別困難 (LC + MS² で部分解決)、quantification 標準化 (internal standard 依存)、in vivo flux は限定的、pathway analysis は KEGG / Reactome 偏向で immunometabolism cover 不十分

Open Questions

• Spatial metabolomics: MALDI-MSI / DESI imaging で TME compartment 別 metabolite mapping
• Single-cell metabolomics の確立 (現状は 100-1000 細胞単位)
• Functional immunometabolism: in vivo isotope flux の routine 化
• Metabolite-targeted therapy: kynurenine / lactate / itaconate 軸の clinical translation

関連エンティティ

• 補完手法: Proteomics-mass-spec / Bulk-RNA-seq / scRNA-seq / CRISPR-screen
• 関連経路: Metabolic-reprogramming-pathway / Itaconate-immunometabolism-pathway / NRF2-KEAP1-pathway / Oxidative-phosphorylation-pathway / AMPK-LKB1-pathway
• 関連概念: Metabolic-reprogramming / T-cell-exhaustion / Cancer-cachexia / Immunometabolism

関連論文

Basic-Brain metastasis

• Wang et al. CancerRes 2026 — VGF-Mediated mitochondrial remodeling fuels lung adenocarcinoma brain metastasis
• Chafe et al. SciSignal 2026 — Emerging paradigms in the study of brain metastases

Basic-Extracellular vesicles

• Chen et al. ACSApplMaterInterfaces 2016 — Imaging and intracellular tracking of cancer-derived exosomes using single-molecule localization-based super-resolution
• Esmaeili et al. BiochemBiophysResCommun 2024 — Metabolically healthy unhealthy obesity and breast cancer
• Raposo et al. JCellBiol 2013 — Extracellular vesicles exosomes, microvesicles, and friends
• Haraszti et al. JExtracellVesicles 2016 — High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources
• Skotland et al. ProgLipidRes 2017 — Lipids in exosomes current knowledge and the way forward
• Bonjoch et al. SciRep 2017 — REG3beta modifies cell tumor function by impairing extracellular vesicle uptake

Basic-Immunotherapy

• Mitroulis et al. Cell 2018 — Modulation of myelopoiesis progenitors is an integral component of trained immunity
• Chen et al. CellMetab 2026 — 16-h fasting optimizes cancer immunotherapy in mice and humans
• Zhang et al. JNanobiotechnology 2026 — Apigenin based nanoplatform achieves non-small cell lung cancer immunotherapy through glycolysis inhibition and
• Yang et al. Nature 2016 — Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism
• Li et al. SciImmunol 2026 — Citraconate preserves T cell stemness and antitumor immunity

Basic-Neutrophil and myeloid cell

• Hsu et al. Cell 2025 — Neutrophil-derived vesicles control complement activation to facilitate inflammation resolution
• Lim et al. CellRep 2026 — Neutrophil-derived itaconate facilitates tiered pulmonary inflammation via kdm5b-associated epigenetic remodeling in

Basic-Oncogene and genetics

• Stein et al. CancerDiscov 2023 — LKB1-dependent regulation of TPI1 creates a divergent metabolic liability between human and mouse lung adenocarcinoma
• Deribe et al. NatMed 2018 — Mutations in the SWI-SNF coplex induce a targetable dependence on oxidative phosphorylation in lung cancer
• Anusewicz et al. SciRep 2020 — Lung squamous cell carcinoma and lung adenocarcinoma differential gene expression regulation through pathways of notch,

Basic-Others

• Gao et al. CellMetab 2026 — The s100a8a9 complex promotes food intake and prevents adipose tissue loss during cancer cachexia in mice
• Morigny et al. JClinInvest 2026 — Inhibition of ceramide synthesis ameliorates body wasting in a cancer cachexia model
• Rowles et al. NatRevCancer 2026 — Decoding cancer across scales with metabolomics

Clinical-NSCLC-Driver negative

• Zitvogel et al. Science 2018 — The microbiome in cancer immunotherapy Diagnostic tools and therapeutic strategies

Clinical-Others

• Chu et al. NatCancer 2026 — Integrated proteogenomic and metabolomic profiling of acute myeloid leukemias to identify molecular subtypes and