PO.MCB09.06 · 分子与细胞生物学
FFPE人体组织的全面代谢组学分析揭示结直肠癌的关键代谢重编程及相关通路
Comprehensive metabolomic profiling of FFPE human tissues reveals key metabolic reprogramming in colorectal cancer and associated pathways
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摘要 Abstract
中文摘要
引言：福尔马林固定石蜡包埋（FFPE）组织因其卓越的形态学保存能力和便捷的存储条件，对回顾性临床研究具有极高价值，但由于缺乏成熟的样本制备方案以及对代谢物稳定性的担忧，其在代谢组学中的应用受到限制。本研究优化了一种新型FFPE代谢组学工作流程，并利用配对的新鲜冷冻（FF）样本对结果进行验证，以鉴定人类结直肠癌（CRC）中发生改变的代谢特征。
方法：我们分析了12份FFPE人体组织样本，包括来自腺癌患者的6对肿瘤及邻近组织（NAT）标本，同时使用配对的FF样本进行验证。使用新一代质谱平台对极性组分和脂质组分进行了全局代谢组学检测。
结果：代谢谱分析从FFPE组织中检测到2,564种独特代谢物，涵盖200多个类别，技术变异低（中位CV < 5%）。无监督分析显示肿瘤与NAT之间存在清晰区分。统计分析鉴定出200种差异代谢物（|log2(fc)| > 1，p < 0.05）。通路分析揭示了39条改变的通路（p < 0.05），其中肿瘤中二酰基甘油磷酸肌醇上调和三酰基甘油下调是最显著的发现。中心碳代谢物和氨基酸的一致上调表明存在为生物合成和缓冲氧化应激而进行的代谢重编程。FF样本验证显示在鉴定出的最显著命中项和通路上具有一致性，证实了FFPE来源特征的稳健性和生物学相关性。
结论：我们的研究证实FFPE代谢组学分析能够可靠地鉴定人类癌症中显著的代谢扰动，且与FF结果一致。所鉴定的脂质、中心碳和氨基酸代谢改变凸显了CRC中广泛的代谢重编程。FFPE档案是大规模回顾性临床代谢组学研究的宝贵资源，为人类遗传学和疾病的探索性研究以及新型生物标志物的鉴定提供了强有力的途径。
查看英文原文 English abstract
Introduction: Formalin-fixed paraffin-embedded (FFPE) tissues are invaluable for retrospective clinical studies due to superior morphological preservation and easy storage, but their use in metabolomics is limited by a lack of established sample preparation protocols and concerns over metabolite stability. Here we optimized a novel FFPE metabolomic workflow and validated findings with matched fresh-frozen (FF) samples to identify metabolic signatures altered in human colorectal cancer (CRC).
Methods: We analyzed 12 FFPE human tissue samples, comprising 6 paired tumor and Nearby Adjacent Tissue (NAT) specimens from adenocarcinoma patients, alongside matched FF samples for validation. Global metabolomics assays were performed on both polar and lipid fractions using a next-generation mass spectrometry platform.
Results: Metabolic profiling detected 2,564 unique metabolites across 200+ classes from FFPE tissues with low technical variation (median CV < 5%). Unsupervised analyses showed clear tumor-NAT distinctions. Statistical analysis identified 200 differential metabolites (|log2(fc)| > 1, p < 0.05). Pathway analysis revealed 39 altered pathways (p<0.05), with upregulated diacylglycerophosphoinositols and downregulated triacylglycerols in tumors being the most significant findings. Consistent upregulation of central carbon metabolites and amino acids indicated metabolic reprogramming for biosynthesis and oxidative stress buffering. FF sample validation showed concordance across the most significant hits and pathways identified, confirming the robustness and biological relevance of FFPE-derived signatures.
Conclusion: Our study confirms FFPE metabolomic profiling reliably identifies significant metabolic perturbations in human cancer, consistent with FF findings. The identified shifts in lipid, central carbon, and amino acid metabolism highlight extensive metabolic reprogramming in CRC. FFPE archives are a valuable resource for large-scale retrospective clinical metabolomics studies, offering a powerful avenue for discovery research in human genetics and disease, and for identifying novel biomarkers.
利益披露 Disclosure
T. Cohen, None..
A. Mehta, None..
A. Richardson, None..
M. Gandhi, None..
D. Guzior, None..
K. Cho, None..
E. Stancliffe, None.