Abstract 4721: Cross-species multi-omics mapping of APC/KRAS-driven metabolic networks

Abstract Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related deaths worldwide. Over 70% of CRCs harbor activating mutations in the EGFR/KRAS and WNT/APC pathway genes, which regulate intestinal stem cells (ISCs) proliferation and differentiation. While these oncogenic pathways are well depicted for their transcriptional effects, their metabolic interactions and cooperative roles in tumor progression remain unclear. Our preliminary data reveal that EGFR signaling promotes ISC self-renewal through an anabolic program that redirects carbohydrates to biosynthetic pathways while using fatty acid oxidation (FAO) to sustain ATP production. Published evidence also suggests that WNT/APC signaling induces similar metabolic changes. Here we show that co-activation of WNT/APC and EGFR/KRAS signaling reprograms cellular metabolism, generating cancer-specific vulnerabilities distinct from those induced by either mutation alone. To test this, we employ an integrated multimodal and multi-omics strategy that combines transcriptomics, metabolomics, lipidomics, and proteomics across Drosophila models and patient-derived organoids (PDOs). This approach maps metabolic changes under normal and oncogenic conditions involving EGFR/RAS and WNT/APC pathways. In Drosophila, ISC-derived cell clones carrying ApcΔ, RasG12V, or dual ApcΔ; RasG12V mutations reveal that dual-hit clones show enhanced proliferation, altered morphology, and cancer-like phenotypes, unlike single hits. Transcriptomic and metabolomic analyses identified distinct differentially expressed genes (DEGs) and metabolic profiles in the dual-hit state, particularly in mitochondrial, lipid, and nucleotide biosynthetic pathways. Integrated multi-omic analyses further identified unique metabolic modules reflecting synergistic reprogramming. Parallel studies in patient-derived cancerous (CRC) organoids show similar patterns: compared to normal control gut organoids, CRC organoids displayed altered morphology, transcription, and metabolism, including reprogrammed lipid and amino acid metabolism and enhanced glycolytic and mitochondrial activity. Following prioritization by evolutionary conservation and multi-omic integration, ∼40 candidate genes (e.g., r, mt:ND4L, eloF, Ak1) will be functionally tested via RNAi or inhibitors in ApcΔ RasG12V Drosophila ISC clones and APC/KRAS colon organoids to assess tumor-suppressive effects. Validated effectors will be evaluated in mouse and xenograft models to identify targetable metabolic dependencies. Together, these findings demonstrate that concurrent APC and KRAS mutations establish a unique synergistic metabolic program driving aggressive CRC. By integrating multi-omics and cross-species models, this study is finding conserved, cancer-specific metabolic effectors as promising therapeutic targets in colorectal cancer. Citation Format: Mahima Bharti, Swagata Maity, Marcos Calderon, Peng Zhang, Augustine Takyi, Marco Marchetti, Paul Stewart, Bruce A. Edgar. Cross-species multi-omics mapping of APC/KRAS-driven metabolic networks [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 4721.