Abstract P57: Molecular Underpinnings of Obesity-related Oesophageal Adenocarcinoma (OAC)

Abstract 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. 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 tumourigenesis, 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 elevated toxic lipid metabolites and higher oxidative stress. 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 condition can dynamically 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 tumourigenesis and highlights the potential role of toxic lipid metabolites in cancer initiation. Citation Format: Kho Yun Suen, Aiswarya Padmaja Satheesh, Daryl Chia, Jimmy So, Asim Shabbir, Kong Li Ren, Ashok Venkitaraman. Molecular Underpinnings of Obesity-related Oesophageal Adenocarcinoma (OAC) [abstract]. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86(13_Suppl):Abstract nr P57.