Lysyl Oxidases Suppress Pancreatic Cancer Progression by Inhibiting Focal Adhesion Kinase Signaling

Lysyl oxidases crosslink type I collagen to promote fibrosis and cancer progression in mouse mammary tumor models. Pancreatic ductal adenocarcinomas (PDACs) are highly fibrotic and contain abundant type I collagen with elevated expression of lysyl oxidases. Indeed, inhibition of lysyl oxidases constitute an attractive anti-tumor therapeutic strategy, with several reported preclinical studies demonstrating efficacy at reducing PDAC fibrosis and progression. Yet, lysyl oxidase was first described as an anti-oncogene through its effect of directly suppressing cell transformation by mutant Ras which is present in around 90% of human pancreatic tumors. These prior studies highlight the dual functions, anti-ras and pro-fibrotic, of lysyl oxidases in pancreatic cancer. As a result, clinical trials targeting lysyl oxidase in cancers have demonstrated limited efficacy. Here we examined the effects of perturbation of lysyl oxidase activity or expression using syngeneic orthotopic transplantation models expressing mutant Ras and intravital imaging. Unexpectedly, genetic or pharmacological inhibition of lysyl oxidases increased invasion along collagen fibers and distant metastasis. Furthermore, inhibition of lysyl oxidases promoted focal adhesion kinase (FAK) activity which was required for metastasis. We found that mutant Kras status dictated lysyl oxidase-mediated suppression on FAK signaling in both mouse and human pancreatic cancer cells. These results suggest that the effect of lysyl oxidase on metastasis are dependent on signaling from Ras and FAK. These results strongly caution against inhibiting lysyl oxidases for cancers driven by mutant Ras. Lijuan Sun, Jean Albrengues, John E. Wilkinson, Sarah L. Dallas, Valerie M. Weaver, Mikala Egeblad, Mario A. Shields. Lysyl oxidases suppress pancreatic cancer progression by inhibiting focal adhesion kinase signaling [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 138.