Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Disease, Yunan Geiatric Medical Center, Kunming, Yunnan, China.
Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
Cancer Cell. 2024 Aug 12;42(8):1386-1400.e8. doi: 10.1016/j.ccell.2024.07.005.
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.
血浆和粪便代谢组学在结直肠癌（CRC）进展（正常-腺瘤-CRC）中的变化仍不清楚。在这里，从四个独立的 1251 个人群（422 例 CRC、399 例结直肠腺瘤 [CRA] 和 430 例正常对照 [NC]）中收集了血浆和粪便样本。通过代谢组学分析，鉴定出了在 NC、CRA 和 CRC 中具有一致变化的特征性血浆和粪便代谢物，包括 CRC 丰富的油酸和 CRC 耗尽的异胆酸。油酸在 CRC 细胞、患者来源的类器官和两种小鼠 CRC 模型中表现出促肿瘤作用，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-烯醇酶或法尼醇 X 受体-1 结合，从而调节与癌症相关的途径。临床上，我们建立了一个由 17 种血浆代谢物组成的panel，可在发现和三个验证队列中准确诊断 CRC（AUC=0.848-0.987）。总体而言，我们描述了 CRC 血浆和粪便代谢组学的代谢特征、机制意义和诊断潜力。
