空间代谢组学揭示的人类癌症恶病质中的器官串扰

癌症恶病质（CCX）提出了一个多方面的挑战，其特征是负蛋白质和能量平衡以及全身性炎症反应激活。 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.使用组件，途径富集和相关网络分析进行器官比较。使用Circos评估CCX改变途径中的器官间相关性。在CCX中检测到了组织和血清上的机器学习，作为CCX的潜在诊断生物标志物。在CCX中检测到了代谢途径的改变，其中脂肪组织和肝脏表现出最显着的（P≤0.05）代谢干扰。与对照患者相比，CCX患者在内脏和皮下脂肪组织和肝脏中的代谢活性增加，与肌肉和血清的活性降低形成鲜明对比。碳水化合物，脂质，氨基酸和维生素代谢作为CCX不同器官系统的高度相互作用途径出现。 CCX患者的肌肉组织显示出降低（P≤0.001），而肝脏和脂肪组织的能量电荷增加（P≤0.001）。我们根据严重性和代谢变化对CCX患者进行了分层，发现内脏脂肪组织受到最大影响，尤其是在严重的恶病质病例中。形态分析表明，内脏脂肪组织中的脂肪细胞大小较小（P≤0.05），表明分解代谢过程。我们开发了针对各个器官特有的癌症恶病质的基于组织的分类器，促进了患者血清作为CCX在器官构成中的微创诊断标志物的最低侵入性诊断标记。这项研究先驱对CCX的空间代谢组学，证明了使用血清区分处于器官水平的恶病质状态的可行性。

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.