Abstract 6126: Multiomics integration unveils a shifted balance in the sphingosine-1 phosphate/ceramide rheostat fueled by macrophage immunosuppression in metastatic colorectal cancer

Abstract Background: Thirty years ago, a S1P/ceramide “sphingosine rheostat” model was proposed based on ceramide’s pro-apoptotic vs. sphingosine-1 phosphate (S1P) pro-survival role, where in cancer, the rheostat tilts towards enhanced synthesis of S1P from ceramides, increasing the ratio. Human tumor data supporting the hypothesis, however, are very limited. Objective: To leverage quantitative multi-omics to explore the balance in the synthesis of lipids within the S1P/Ceramide metabolic pathway in a large set (n = 629) of human colorectal cancers (CRC).Design Quantitative LC-MS/MS analysis was performed on 525 primary and 104 metastatic CRC (mCRC). An integrative multi-omics analysis combining quantitative lipidomics with whole transcriptomics, quantitative RT-PCR of selected genes and clinical data was completed. Results: We demonstrated that mCRC versus primary specimens are relatively enriched in S1P and sphinganine-1-P (Sa1P), whereas the long chain ceramides (24:1) are relatively decreased. Gene-expression analysis of a large (n = 2200) CRC patient dataset and qRT-PCR of CRC revealed that S1P/Sa1P-synthesizing enzymes and their receptors are enriched in mCRC and are linked to poor prognosis. scRNA-seq analysis showed that their expression prevailed in myeloid cells. Finally, a three-gene S1P macrophage-associated signature correlated with stage and patient survival. Conclusion: Our findings define an imbalance in the synthesis of S1P/Ceramide linked to poor prognosis and cancer progression, and attributable to proinflammatory macrophages in the tumor microenvironment, validating the sphingosine rheostat hypothesis in mCRC. Citation Format: Michelle M. Maurin, Siddabasave Gowda B. Gowda, Divyavani Gowda, Heiman Wang, Michael Nebozhyn, Ramani Soundararajan, Mckayla Carr, Punith M Sundaraswamy, Ashley Alden, Carolina Martinez, Robert David Bennett, Allen Chudzinski, Andreas Karachristos, Timothy M. Nywening, Paul M. Cavallaro, Matthew Linley Anderson, Robert J. Coffey, Michael Schell, Jorge Marcet, Richard Jacobson, Andrey Loboda, Ganesh V. Halade, Mingli Yang, Lance Pflieger, Warren Jackson Pledger, Shu-Ping Hui, Timothy J. Yeatman. Multiomics integration unveils a shifted balance in the sphingosine-1 phosphate/ceramide rheostat fueled by macrophage immunosuppression in metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6126.