Integrative plasma and fecal metabolomics identify functional metabolites in adenoma-colorectal cancer progression and as early diagnostic biomarkers

IF 48.8 1区医学 Q1 CELL BIOLOGY Cancer Cell Pub Date : 2024-08-12 DOI:10.1016/j.ccell.2024.07.005

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Abstract

Changes in plasma and fecal metabolomes in colorectal cancer (CRC) progression (normal-adenoma-CRC) remain unclear. Here, plasma and fecal samples were collected from four independent cohorts of 1,251 individuals (422 CRC, 399 colorectal adenoma [CRA], and 430 normal controls [NC]). By metabolomic profiling, signature plasma and fecal metabolites with consistent shift across NC, CRA, and CRC are identified, including CRC-enriched oleic acid and CRC-depleted allocholic acid. Oleic acid exhibits pro-tumorigenic effects in CRC cells, patient-derived organoids, and two murine CRC models, whereas allocholic acid has opposing effects. By integrative analysis, we found that oleic acid or allocholic acid directly binds to α-enolase or farnesoid X receptor-1 in CRC cells, respectively, to modulate cancer-associated pathways. Clinically, we establish a panel of 17 plasma metabolites that accurately diagnoses CRC in a discovery and three validation cohorts (AUC = 0.848–0.987). Overall, we characterize metabolite signatures, mechanistic significance, and diagnostic potential of plasma and fecal metabolomes in CRC.

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整合血浆和粪便代谢组学发现腺瘤-结直肠癌进展过程中的功能代谢物和早期诊断生物标记物

大肠癌（CRC）进展期（正常-腺瘤-CRC）血浆和粪便代谢组的变化仍不清楚。本文收集了来自四个独立队列 1,251 人（422 例 CRC、399 例结直肠腺瘤 [CRA] 和 430 例正常对照 [NC]）的血浆和粪便样本。通过代谢组学分析，确定了在 NC、CRA 和 CRC 中发生一致转变的特征性血浆和粪便代谢物，包括 CRC 富集的油酸和 CRC 贫乏的别胆酸。油酸在 CRC 细胞、患者衍生的器官组织和两种小鼠 CRC 模型中具有促肿瘤作用，而异胆酸则具有相反的作用。通过综合分析，我们发现油酸或异胆酸分别直接与 CRC 细胞中的α-烯醇化酶或法尼类固醇 X 受体-1 结合，从而调节癌症相关通路。在临床上，我们建立了一个由 17 种血浆代谢物组成的面板，可在一个发现组和三个验证组中准确诊断出 CRC（AUC = 0.848-0.987）。总之，我们描述了 CRC 中血浆和粪便代谢组的代谢物特征、机理意义和诊断潜力。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.