空间代谢组学揭示的人类癌症恶液质中的器官间交互作用

癌症恶液质（CCx）表现为多方面的挑战，具有蛋白质和能量的负平衡以及系统性炎症反应激活。尽管以往的CCx研究主要集中在小鼠模型或人体体液，但仍迫切需要阐明人类CCx的发病机制中的分子器官间交互作用。我们在恶液质和对照癌症患者的肝脏、骨骼肌、皮下脂肪、内脏脂肪组织及血清上进行了空间代谢组学分析。通过组分分析、通路富集和相关网络分析，对不同器官的比较进行了评估。利用Circos分析器官间的相关性，评价CCx中途径的变化。基于机器学习的模型在组织和血清中建立了潜在的诊断生物标志物。发现CCx中存在明显的代谢途径变化，脂肪组织和肝脏表现出最显著的代谢紊乱（P ≤ 0.05）。CCx患者表现出内脏和皮下脂肪组织以及肝脏的代谢活性增强，而肌肉和血清的代谢活性则相对降低。碳水化合物、脂质、氨基酸和维生素的代谢成为不同器官系统间高度交互的通路。肌肉组织中的能量储备（能量指标）在CCx患者中显著降低（P ≤ 0.001），而肝脏和脂肪组织的能量指标则升高（P ≤ 0.001）。我们根据严重程度和代谢变化对CCx患者进行分层，发现内脏脂肪组织受影响最大，尤其在严重恶液质病例中。形态测量显示内脏脂肪组织中脂肪细胞尺寸较小（P ≤ 0.05），提示分解代谢过程。我们建立了针对不同器官的组织基础分类模型，有助于利用患者血清作为非侵入性诊断标志物，反映器官内的CCx状态。这些发现支持将CCx视为多器官综合征，伴随多样的代谢改变，为人类CCx的发病机制和器官间交互作用提供了新的见解。本研究开创了空间代谢组学在CCx中的应用，展示了利用血清在器官水平区分恶液质状态的可行性。

Cancer cachexia (CCx) presents a multifaceted challenge characterized by negative protein and energy balance and systemic inflammatory response activation. While previous CCx studies predominantly focused on mouse models or human body fluids, there's an unmet need to elucidate the molecular inter-organ cross-talk underlying the pathophysiology of human CCx.Spatial metabolomics were conducted on liver, skeletal muscle, subcutaneous and visceral adipose tissue, and serum from cachectic and control cancer patients. Organ-wise comparisons were performed using component, pathway enrichment and correlation network analyses. Inter-organ correlations in CCx altered pathways were assessed using Circos. Machine learning on tissues and serum established classifiers as potential diagnostic biomarkers for CCx.Distinct metabolic pathway alteration was detected in CCx, with adipose tissues and liver displaying the most significant (P ≤ 0.05) metabolic disturbances. CCx patients exhibited increased metabolic activity in visceral and subcutaneous adipose tissues and liver, contrasting with decreased activity in muscle and serum compared to control patients. Carbohydrate, lipid, amino acid, and vitamin metabolism emerged as highly interacting pathways across different organ systems in CCx. Muscle tissue showed decreased (P ≤ 0.001) energy charge in CCx patients, while liver and adipose tissues displayed increased energy charge (P ≤ 0.001). We stratified CCx patients by severity and metabolic changes, finding that visceral adipose tissue is most affected, especially in cases of severe cachexia. Morphometric analysis showed smaller (P ≤ 0.05) adipocyte size in visceral adipose tissue, indicating catabolic processes. We developed tissue-based classifiers for cancer cachexia specific to individual organs, facilitating the transfer of patient serum as minimally invasive diagnostic markers of CCx in the constitution of the organs.These findings support the concept of CCx as a multi-organ syndrome with diverse metabolic alterations, providing insights into the pathophysiology and organ cross-talk of human CCx. This study pioneers spatial metabolomics for CCx, demonstrating the feasibility of distinguishing cachexia status at the organ level using serum.