OR04-03 Using integrative lipid systems biology to understand adrenocortical cancer

Abstract Disclosure: S. Jarvis: None. L. Gethings: None. L. Reid: None. M. Towers: None. W. Arlt: None. C.L. Ronchi: None. C. Bevan: None. Introduction: Adrenocortical carcinoma (ACC) is a rare and highly aggressive tumour with many patients presenting at advanced stages. Although the molecular pathogenesis has been partially clarified by previous multi-omics studies, effective targeted therapeutics are still lacking. ACC can be classified as a lipid poor cancer on cross sectional imaging and histology. We performed a comprehensive analysis of ACC-specific lipid signatures to gain new insights into the pathogenesis and progression of this disease. Methods: Human snap-frozen adrenocortical tumour tissues (n=9 adenomas and n=12 ACC) were used for liquid chromatography-mass spectrometry (LC-MS) studies using ACQUITY Premier LC coupled to a Xevo MRT mass spectrometer. MS data were processed using MS-DIAL, for peak picking, normalisation and lipid identification. MS imaging (MSI) was undertaken with a DESI SYNAPT G2-Si and Waters High-Definition Imaging (HDI) 1.4 with MassLynx software. Additionally, qRT-PCR was undertaken on the same adrenal tissues to identify key lipid genes dysregulated in ACC to generate a deeper understanding of gene-metabolite relationships. Demographics and clinical data were collected for all cases. Results: Multivariate analysis indicated significant differences in the lipidome of adenomas vs ACC. Combined multi-modal lipidomic strategies (LC-MS and MSI), identified the main lipid species responsible for these differences in ceramides, sphingomyelins and phospholipid species. MSI-generated spatial lipidomics revealed heterogeneity in the various lipid species across ACC tissues. Gene expression analysis confirmed upregulation of BUB1B (p=0.0004), a known ACC marker, and significant downregulation in genes related to lipid metabolism (LXR, SREBP1c, ABCA1, APOE, p<0.01) in ACC compared to adenomas.Conclusions: We identify several metabolites and lipid signature genes to be highly dysregulated in ACC. Our results provide novel insights into the lipid signature in ACC, providing an important basis to improve understanding of lipid metabolism in ACC. Additional studies are ongoing to further interrogate lipid pathways in adrenocortical tumours. Presentation: Saturday, July 12, 2025