Key result
Obesity and high lipid environments link to oxidative stress and genomic instability in oesophageal models.
Why the study?
Epidemiological studies show a strong link between obesity and increased risk of oesophageal adenocarcinoma, but the underlying mechanism remains poorly understood.
Observational
Obesity-associated oesophageal adenocarcinoma may be driven by lipid-mediated metabolic and genomic dysregulation, with toxic lipid metabolites potentially contributing to cancer initiation.
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.
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Suen et al. (2026) conducted an observational in Obesity-related Oesophageal Adenocarcinoma (OAC). Obesity and high lipid environment vs. Non-obese individuals and lipid withdrawal conditions was evaluated on Metabolic and genomic alterations including lipid metabolism, oxidative stress, and tumour mutational burden. Obesity and high lipid environments were associated with dysregulated lipid metabolism, higher oxidative stress, and increased genomic instability in oesophageal tissues and organoid models.
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