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Inter-organ cross-talk in human cancer cachexia revealed by spatial metabolomics.
Metabolism 161:156034 (2024)
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Cancer Cachexia Patients ; Diagnostics Of Cachexia ; Inter-organ Cross-talk ; Machine Learning ; Metabolomics Classifier ; Spatial Metabolomics; Mass-spectrometry; Adipose-tissue; Inflammation; Muscle; Metabolites; Environment; Dysfunction; Mechanisms; Serotonin; Mice
ISSN (print) / ISBN
0026-0495
e-ISSN
1532-8600
Quellenangaben
Volume: 161,
Article Number: 156034
Publisher
Elsevier
Publishing Place
1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Research Unit Analytical Pathology (AAP)
Grants
NIDDK
Novo Nordisk Foundation
German Center of Infection Research (DZIF)
Else Kroner-Fresenius-foundation, Bad Homburg
Deutsche Forschungsgemeinschaft
Ministry of Education and Research of the Federal Republic of Germany (BMBF)
Novo Nordisk Foundation
German Center of Infection Research (DZIF)
Else Kroner-Fresenius-foundation, Bad Homburg
Deutsche Forschungsgemeinschaft
Ministry of Education and Research of the Federal Republic of Germany (BMBF)