Abstract A030: Defining the role of ceramide metabolism in clear cell renal cell carcinoma progression

Abstract Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, has been strongly associated with dysregulated lipid metabolism in obesity, known to contribute to ccRCC development. The mechanisms connecting obesity to ccRCC initiation and progression remain unclear. Ceramides, bioactive sphingolipids, influence mitochondrial function, metabolism, and cell fate. However, their role in ccRCC initiation and progression is not understood. We hypothesized that ceramides are essential intermediates linking lipid excess to the onset and progression of ccRCC. We leveraged lipidomics and transcriptomics data from the KidneyCare Study, a prospective cohort study that recruited 162 patients undergoing nephrectomy for a renal mass (stage I-IV) at the Huntsman Cancer Institute, University of Utah. After excluding 6 patients with systemic therapy prior to surgery, 68 patients with ccRCC had flash-frozen for downstream omics analyses. Targeted sphingolipid quantification was performed by LC-MS/MS using multiple reaction monitoring (MRM) and RNA sequencing (RNAseq). Among 47 normal and 72 tumor samples, we profiled 119 sphingolipids. We performed differential sphingolipid expression analysis and Lipid Ontology (LION) enrichment analysis comparing tumor vs. normal tissue lipids, and multi-omics analysis using integrative module analysis for multi-omics data (iModMix) integrating sphingolipids and RNAseq data to identify correlated features distinguishing tumor from normal tissue. A total of 79/119 (66%) sphingolipids were differentially expressed between tumor and normal tissue (t-test padjj < 0.05, > 1.5 fold-change). We found the ceramide Cer18:1;O2/24:1 (Cer 24:1) to be overexpressed in tumor vs. normal tissue. Cer 24:1 ceramides are directly associated with poor metabolic health, cardiovascular disease, and mortality. Applying iModMix identified 82 gene modules and 12 sphingolipid modules with ceramide modules being the most abundant. Highly correlated ceramides and transcriptomics module pairs included cell signaling pathways and lipid-related metabolic pathways. Our findings suggest that ceramide metabolism is significantly altered in ccRCC tumor vs. normal kidney. In the future, we will explore the potential link between Cer 24:1 overexpression and ccRCC progression. Citation Format: Augustine Takyi, Kyle Harshany, Gabriela Sandri, Olivia Rodriguez, Adam Taylor, Rebekah Nicolson, Christopher Dechet, Bogdana Schmidt, Brock O’Neil, Mei Koh, Scott Summers, Katsuhiko Funai, Mary Playdon, Cornelia Ulrich, John Alan. Maschek, Bing-Jian Feng, Paul Stewart, Alejandro Sanchez. Defining the role of ceramide metabolism in clear cell renal cell carcinoma progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr A030.