Dysregulated lipid metabolism accompanies chromosomal instability in obesity-associated oesophageal adenocarcinoma

Background - The global rise in obesity has been paralleled with increasing incidence of obesity-associated cancers, including OAC. While epidemiological studies have shown a strong link between obesity and increased risk of OAC, the underlying mechanism remains poorly understood. We hypothesized that toxic metabolites associated with obesity can induce chromosomal instability, thereby provoking carcinogenesis in OAC. Method - To investigate obesity-associated metabolic and genomic alterations in OAC, we performed metabolomics, immunohistochemistry (IHC) and whole-genome sequencing on paired malignant and non-malignant gastroesophageal junction (GEJ) tissues from individuals with varying body mass index (BMI). To model early events during obesity-associated tumorigenesis, we have developed long-term organoid cultures from normal simple columnar epithelial biopsies obtained during bariatric surgeries, to test the effects of long-term growth in a high lipid environment. Results - Our preliminary results suggested an association between obesity and dysregulated lipid metabolism in both non-malignant and OAC tissues. Obese non-malignant tissues showed an elevation in toxic lipid metabolite, 4-hydroxy-2-nonenal (4-HNE) and higher oxidative stress with elevated oxidative DNA damage markers. Obese tumour tissues exhibited a higher tumour mutational burden and genomic instability score, suggesting that obesity may result in a distinct, genomically unstable OAC subtype. To recapitulate these obesity-associated alterations, organoids were grown in a high lipid environment. Prolonged culture induced morphological changes, with reduced differentiation markers and increased stemness. Notably, lipid withdrawal restored the organoid morphology, demonstrating that lipid-rich conditions can transiently alter epithelial cell states and may contribute to tumour initiation. Conclusion - Our preliminary results suggest the existence of an obesity-associated OAC subtype driven by lipid-mediated metabolic and genomic dysregulation. The organoid model serves as an in vitro platform for dissecting early events in obesity-associated tumorigenesis and highlights the potential role of toxic lipid metabolites in cancer initiation.