Adipose tissue metabolomics identifies disease stage and tumour invasiveness of rectal cancer

Abstract Backgorund Adipose tissue has emerged as a prognostic factor in rectal cancer (RC), yet its metabolic role in tumour progression remains poorly understood. This study aims to characterise the metabolic profiles of subcutaneous (SAT) and visceral adipose tissue (VAT) in early and advanced tumours to investigate metabolic alterations that may influence tumour progression. Understanding these alterations could provide insights into mechanisms of rectal cancer and identify therapeutic targets. Methods Global metabolic profiles of 68 SAT and VAT samples from patients with RC were analyzed using high‐performance chemical isotope labeling liquid chromatography mass spectrometry. Statistical analyses were stratified by clinical tumour invasion and disease stage. Results VAT exhibited distinct metabolic signatures between early and advanced tumour invasion. Advanced tumours (cT3‐4) had a higher concentration of N‐glycolylneuraminic acid and phenylacetylglutamine, whereas early invasive tumours (cT2) exhibited higher levels of dipeptides. Pathway enrichment analyses revealed dysregulations in taurine and hypotaurine metabolism, alanine, aspartate and glutamate metabolism, propanoate metabolism and cellular signalling pathways in advanced invasion. Propanoate metabolism emerged as a key pathway distinguishing early and advanced invasion stages. In SAT, metabolic changes aligned with overall disease stage. Early‐stage disease was associated with a higher concentration of dipeptides, whereas advanced stages showed increased N‐acetyl‐agmatine and N‐acetyl‐L‐noradrenaline. Conclusions Our study highlights significant metabolic alterations in adipose tissue associated with rectal cancer progression. VAT metabolism reflects tumour invasiveness, while SAT is more indicative of disease stage. Propanoate metabolism may serve as a biomarker for advanced invasion, offering potential for improved staging, reclassification and personalised therapeutic strategies.