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

Cancer research in veterinary medicine is still under development compared to human medicine. Feline breast cancer (FBC) is highly malignant, intractable, and has the potential to become a valuable model for human metastatic BC (HBC). We developed primary FBC organoids and analyzed their morphology, gene expression patterns, and response to anti-cancer drugs. FBC 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 FBC organoid lines. Furthermore, LMTK3 was significantly upregulated in FBC organoids compared to feline normal mammary organoids (FNM). Further, LMTK3/FADS2 pathway was revealed to be implicated in progression and metastasis by influencing cell proliferation, invasion, and apoptosis of FBC organoids. Treatment with C28 (an LMTK3 inhibitor) also prevented cell viability of human BC organoids. The 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 FBC organoid might help to do comparative research, and identify conserved mechanisms between HBC and FBC.