Abstract 4152: Disrupting lipid elongation impairs prostate cancer progression in c-MYC driven mouse models

Abstract Background: Altered lipid metabolism is a hallmark of prostate cancer development and progression. Key pathways affected include de novo fatty acid synthesis and downstream fatty acid elongation, which are both activated by androgens and oncogenic signaling, including c-Myc, a downstream target of Fatty Acid Synthase. One of the enzymes that is upregulated in clinical PCa is ELOVL5 (Elongation of Very Long-Chain Fatty Acids Protein 5), a target of the androgen receptor (AR), which catalyzes the initial step of fatty acid elongation. However, its role in cancer progression remains unknown. Methods: Prostate tumors from HiMyc transgenic mice were evaluated for growth, histopathological progression and lipidomics changes up to 48 weeks and compared to HiMyc mice with ELOVL5 homozygous deletion. 3D organoid model derived from the ventral prostate of these GEMMs were assessed for changes in cell proliferation, size, and response to anti-androgen therapy (Enzalutamide). Rescue experiments were performed by supplementation with cis-vaccenic acid, a key fatty acid product of ELOVL5 activity. Results: ELOVL5 KO significantly inhibited progression from prostatic intraepithelial neoplasia to invasive adenocarcinoma in comparison to HiMyc mice. Lipidomic profiling confirmed reduced levels of ELOVL5 elongation products, characterized by shortened acyl chains in phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, in both serum and prostate tissues. The growth effect was recapitulated in organoids derived from these mice, was further enhanced by Enzalutamide and partially rescued by supplementation with cis-vaccenic acid. Gene expression profiling confirmed downregulation of fatty acid biosynthesis pathways and androgen receptor in HiMyc: ELOVL5 KO models. Conclusion: ELOVL5 curtails c-Myc-driven prostate cancer, providing a direct link between fatty acid elongation and prostate cancer progression. Citation Format: Silvia D. Rodrigues, Isadora F. Teixeira, Giuseppe N. Fanelli, Caroline F. Ribeiro, Fabio Socciarelli, Jeanne Jiang, Debora C. Bastos, Hubert Pakula, Filippo Pederzoli, Pier V. Nuzzo, Alessandro Barberis, Lisa M. Butler, Johannes V. Swinnen, Massimo Loda. Disrupting lipid elongation impairs prostate cancer progression in c-MYC driven mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4152.