Abstract B44: Lysyl oxidases suppress pancreatic cancer progression and inhibit FAK and ERK signaling

Abstract

Abstract Pancreatic cancer carries a dismal prognosis, as most patients present with locally advanced and metastatic disease at time of diagnosis. High levels of type I collagen extracellular matrix in pancreatic tumor specimens are associated with poor survival and resistance to therapy. Furthermore, the expression of lysyl oxidases (LOXs), enzymes that mediate cross-linking and linearization of collagen type I, correlate with poor prognosis in breast and pancreatic cancer. However, a clinical trial targeting LOX-like (LOXL) 2 in pancreatic cancer did not show any survival benefits, pointing to a limited understanding of the context in which these enzymes function in cancer progression. To understand how collagen structure influences cancer cell behavior, we used host mice that expressed GFPtopaz fused to collagen type I and performed intravital microscopy after orthotopic injection of fluorescently labeled cancer cells (derived from the KPC mouse models of pancreatic cancer). Strikingly, we observed that invasive cancer cells migrated out of the tumors on linear type I collagen. Surprisingly, inhibition of LOX and LOXL2, using a pharmacologic inhibitor or shRNA-mediated knockdown, had the opposite results of what we expected with increased metastasis, collagen linearization, and focal adhesion kinase (FAK) activity. Indicating a mechanism independently of collagen crosslinking, LOX inhibition promoted invasion and increased FAK and Ras/ERK-MAPK signaling in vitro, when cells were grown on plastic. We demonstrated that the FAK activity was required for the increased metastasis induced by LOX inhibition, using a clinical stage pharmacologic inhibitor. Our data highlight that LOXs in pancreatic cancer play an important role in suppression of the ERK and FAK signaling pathways, and metastasis. Indeed, the earliest report of lysyl oxidase function in cancer was as a tumor suppressor in Ras transformed cells. Citation Format: Mario Shields, Pascal Maguin, Christopher Giuliano, Sarah Dallas, John Erby Wilkinson, Mikala Egeblad. Lysyl oxidases suppress pancreatic cancer progression and inhibit FAK and ERK signaling [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B44.