Abstract 3063: Defining oncogene-specific metabolic vulnerabilities in a mouse model of hepatocellular carcinoma

Abstract Despite the continued success of advanced cancer therapies, hepatocellular carcinoma (HCC) represents a substantial challenge to current treatment modalities that are not sufficiently effective for the management of advanced disease. Metabolic reprogramming is a hallmark of cancer and many oncogenic signaling pathways impact on cellular metabolism. Here, we are investigating changes in metabolism in different oncogene-driven mouse models of liver cancer to identify selective metabolic vulnerabilities associated with HCC that could be implicated in tumor initiation and progression to be exploited for cancer therapy. Transposon-based vectors coding for different combinations of oncogenes, either Myc and Akt1Myr (CaMIA) or Myc and NrasG12V (CaMIN), were transduced by hydrodynamic tail vein injected into C57BL/6 mice. The resulting liver tumors and control livers were subjected to a comprehensive profiling of polar metabolites (metabolomics) and lipids (lipidomics and total fatty acids) as well as changes in gene expression (transcriptomics). Despite similar overall survival, the two models display marked differences in the presentation of the tumors, with CaMIA showing larger aggressive tumors, while CaMIN livers contain numerous small tumor nodules. Both models also showed evidence for the deregulation of intermediate metabolism, indicating activation of aerobic glycolysis and deregulation of glutamine metabolism. Lipidomic analysis revealed substantial lipidome remodeling in both models. Oncogene-specific alterations included elevated levels of lysophosphatidylcholine (LPC) in CaMIN tumors, while CaMIA tumors displayed high levels of ether phospholipids compared to CaMIN and normal liver. Moreover, the fraction of polyunsaturated fatty acids (PUFAs) was enhanced in lipids from CaMIN tumors, while monounsaturated fatty acids (MUFAs) were enriched in CaMIA tumors. Furthermore, tumors from both genotypes produced higher levels of oxylipins, a class of lipid mediators involved in signaling and inflammation, compared to normal liver. Transcriptome analysis confirmed these metabolic alterations and revealed evidence for enhanced inflammatory signaling in CaMIN. In addition, analysis of tumor microenvironment composition disclosed specific differences in stromal components, indicative of immune evasion through checkpoint activation. Experiments in primary murine liver cancer cell lines confirmed oncogene-specific metabolic rearrangements and suggest elevated sensitivity towards inhibitors of lipid remodeling. Future experiments will investigate the role of altered lipid metabolism in tumor development and immune evasion in liver cancer. Citation Format: Kamal Al-Shami, Marteinn Snaebjornsson, Felix Vogel, Lisa Schlicker, Phillip Pöller, Daniel Dauch, Almut Schulze. Defining oncogene-specific metabolic vulnerabilities in a mouse model of hepatocellular carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3063.