Abstract 28: Novel organoid-based exploration reveals the role of LMTK3/FADS2 signaling in metastatic breast cancer progression in cats and humans

Abstract Cat breast cancer (CBC) is the third most common type of feline neoplasm. It constitutes approximately 17% of feline tumors, with an estimated annual incidence of between 13 and 25/100, 000 cats. CBC shares similar histology, genetics, behavior, and clinicopathological characteristics with human BC. Despite advancements in human breast cancer (BC) treatment, outcomes in human and veterinary medicine remain suboptimal. Spontaneously developed BC in CBC is highly malignant, intractable, and has the potential to become a valuable translational model for human metastatic BC (HBC). We developed primary CBC organoids and analyzed their morphology, gene expression patterns, and response to anti-cancer drugs. CBC organoids recapitulated the structure and behavior of tumor cells, exhibiting diverse hormone receptor expressions and tumorigenic potential. Moreover, varying sensitivities to chemotherapies and targeted drugs were evident across CBC organoid lines. Furthermore, LMTK3 was significantly upregulated in CBC organoids compared to normal organoids. Further, LMTK3/FADS2 pathway was revealed to be implicated in progression and metastasis by influencing cell proliferation, invasion, and apoptosis of CBC organoids. Cell viability of human BC organoids was also prevented by treatment of LMTK3 inhibitor. Survival time of human BC patients with high co-expression of LMTK3 and FADS2 was shorter than that with low co-expression. These findings highlight the importance of LMTK3/FADS2 pathway in BC progression and indicate that companion animal cancer organoid research can model HBC. Citation Format: Haru Yamamoto, Mohamed Elbadawy, Tatsuya Usui, Kazuaki Sasaki. Novel organoid-based exploration reveals the role of LMTK3/FADS2 signaling in metastatic breast cancer progression in cats and humans [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 28.