Background
Obesity is a major risk factor for aggressive colorectal cancer (CRC), yet how dysfunctional adipose tissue shapes tumor behavior remains unclear. In particular, the role of obesity-associated adipocytes in driving tumor metabolic heterogeneity and phenotypic plasticity is poorly defined. Here, we investigated whether hypertrophic adipocytes establish a metabolic niche that promotes distinct metabolic states and invasive phenotypes in CRC cells through direct cell–cell communication.
Methods
HCT-116 CRC cells were co-cultured with SGBS human adipocytes differentiated into mature or hypertrophic (obese) phenotypes. Untargeted LC–MS metabolomics was conducted on tumor lysates, adipocyte lysates, and conditioned media. Multivariate (PCA, PLS-DA) and univariate statistical approaches (Welch’s ANOVA with Games–Howell post hoc correction) identified differential metabolites and pathway alterations. Western blotting assessed ECM components (fibronectin, integrin α5), fatty acid oxidation (CPT1A), lipogenesis (FASN), and oncogenic signaling (Akt/mTOR).
Results
Adipocyte–tumor interaction induced profound metabolic reprogramming, evidenced by elevated glycolytic intermediates, altered TCA cycle flux (increased citrate and α-ketoglutarate; decreased malate), and enhanced glutaminolysis (glutamate/glutamine accumulation). Metabolic exchange was pronounced in supernatants, showing glucose depletion alongside elevated lactate, succinate, methionine, and purine metabolites. Notably, hypertrophic adipocytes specifically upregulated fibronectin, integrin α5, CPT1A, and FASN expression, concomitant with Akt/mTOR activation, linking lipid-rich microenvironments to invasive signaling.
Conclusions
These findings demonstrate that obesity-associated adipocytes actively reshape the tumour microenvironment by promoting metabolic heterogeneity in CRC, characterized by enhanced glycolysis, glutaminolysis, and ECM remodeling. This adipocyte–tumour metabolic axis drives invasive phenotypes and highlights actionable metabolic vulnerabilities for therapeutic intervention.
