PO.MCB09.06 · 分子与细胞生物学
脂质代谢失调伴随肥胖相关食管腺癌中的染色体不稳定
Dysregulated lipid metabolism accompanies chromosomal instability in obesity-associated oesophageal adenocarcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景——全球肥胖率的上升与包括OAC在内的肥胖相关癌症发病率的增加相平行。虽然流行病学研究已显示肥胖与OAC风险增加之间存在密切联系，但其潜在机制仍知之甚少。我们假设与肥胖相关的毒性代谢物可诱导染色体不稳定，从而引发OAC的癌变。
方法——为研究OAC中肥胖相关的代谢和基因组改变，我们对来自不同体重指数（BMI）个体的配对恶性和非恶性胃食管交界处（GEJ）组织进行了代谢组学、免疫组织化学（IHC）和全基因组测序。为模拟肥胖相关肿瘤发生过程中的早期事件，我们从减重手术期间获得的正常单柱状上皮活检组织中开发了长期类器官培养，以测试在高脂质环境中长期生长的效应。
结果——我们的初步结果提示在非恶性和OAC组织中肥胖与脂质代谢失调之间存在关联。肥胖的非恶性组织显示毒性脂质代谢物4-羟基-2-壬烯醛（4-HNE）升高，以及更高的氧化应激伴氧化性DNA损伤标志物升高。肥胖肿瘤组织表现出更高的肿瘤突变负荷和基因组不稳定评分，提示肥胖可能导致一种独特的、基因组不稳定的OAC亚型。为重现这些肥胖相关的改变，将类器官在高脂质环境中培养。长期培养诱导了形态变化，分化标志物减少，干性增强。值得注意的是，撤除脂质恢复了类器官形态，表明富脂条件可短暂改变上皮细胞状态，并可能促进肿瘤起始。
结论：我们的初步结果提示存在一种由脂质介导的代谢和基因组失调驱动的肥胖相关OAC亚型。该类器官模型作为剖析肥胖相关肿瘤发生早期事件的体外平台，并强调了毒性脂质代谢物在癌症起始中的潜在作用。
查看英文原文 English abstract
Background - The global rise in obesity has been paralleled with increasing incidence of obesity-associated cancers, including OAC. While epidemiological studies have shown a strong link between obesity and increased risk of OAC, the underlying mechanism remains poorly understood. We hypothesized that toxic metabolites associated with obesity can induce chromosomal instability, thereby provoking carcinogenesis in OAC.
Method - To investigate obesity-associated metabolic and genomic alterations in OAC, we performed metabolomics, immunohistochemistry (IHC) and whole-genome sequencing on paired malignant and non-malignant gastroesophageal junction (GEJ) tissues from individuals with varying body mass index (BMI). To model early events during obesity-associated tumorigenesis, we have developed long-term organoid cultures from normal simple columnar epithelial biopsies obtained during bariatric surgeries, to test the effects of long-term growth in a high lipid environment.
Results - Our preliminary results suggested an association between obesity and dysregulated lipid metabolism in both non-malignant and OAC tissues. Obese non-malignant tissues showed an elevation in toxic lipid metabolite, 4-hydroxy-2-nonenal (4-HNE) and higher oxidative stress with elevated oxidative DNA damage markers. Obese tumour tissues exhibited a higher tumour mutational burden and genomic instability score, suggesting that obesity may result in a distinct, genomically unstable OAC subtype. To recapitulate these obesity-associated alterations, organoids were grown in a high lipid environment. Prolonged culture induced morphological changes, with reduced differentiation markers and increased stemness. Notably, lipid withdrawal restored the organoid morphology, demonstrating that lipid-rich conditions can transiently alter epithelial cell states and may contribute to tumour initiation.
Conclusion - Our preliminary results suggest the existence of an obesity-associated OAC subtype driven by lipid-mediated metabolic and genomic dysregulation. The organoid model serves as an in vitro platform for dissecting early events in obesity-associated tumorigenesis and highlights the potential role of toxic lipid metabolites in cancer initiation.
利益披露 Disclosure
Y. Kho, None..
A. Nair, None..
D. K. Chia, None..
S. Srivastava, None..
J. B. So, None..
A. Shabbir, None..
L. Kong, None.
A. R. Venkitaraman,
ARV is a member of the Scientific Advisory Board of Chugai Pharmaceuticals Ltd., Japan, and a Director of Chugai Pharmabody Research Ltd., Singapore. g., Board of Directors, non-salaried role).