Abstract
Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a 5-year survival rate of only 6%. Despite advances in conventional therapies and targeted therapies, survival has not improved in the past three decades. We found that high expression of LOX (Lysyl Oxidase) is a poor prognostic marker in PDAC, suggesting a role in this disease. LOX is an amine oxidase that catalyzes the cross-linking of collagens and elastin in the extracellular matrix (ECM) thus regulating extracellular stiffness and contributing to desmoplasia (abundant fibrotic stroma). LOX inhibition has been associated with decreased phosphorylation of SRC (Proto-oncogene tyrosine-protein kinase Src) and FAK (Focal Adhesion Kinase) as a result of decreased interaction of integrins with the ECM. To further investigate the role of LOX in pancreatic cancer, we obtained PDAC cells derived from a transgenic mouse model that faithfully recapitulates the human disease. We found that LOX was upregulated in tumor cells from Pdx1-Cre KrasG12D/+ Trp53R172H/+ (KPC) mice compared to Pdx1-Cre KrasG12D/+ (KC) mice. Using a genetic approach we developed LOX-relevant models by silencing LOX in KPC cells via shRNA and overexpressing LOX in KC cells. We characterized these cells for their invasion ability and growth in a 3D environment. We then confirmed these in vitro results in allograft models in mice. Collectively, our results validate LOX as a therapeutic target in PDAC and suggest that its inhibition represents a new therapeutic strategy for PDAC patients. Citation Format: Grazia Saturno, Filipa Lopes, Amaya Viros, Jennifer Morton, Owen Sansom, Caroline Springer, Richard Marais. Lysyl Oxidase a therapeutic target in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2677. doi:10.1158/1538-7445.AM2014-2677
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