Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy

Miller, B. W. et al. (2015) Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Molecular Medicine, 7, pp. 1063-1076. (doi: 10.15252/emmm.201404827) (PMID:26077591) (PMCID:PMC4551344)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer‐related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1‐Cre KrasG12D/+ Trp53R172H/+ (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor‐free survival in KPC mice with early‐stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jamieson, Professor Nigel and Bailey, Dr Peter and Shanks, Dr Emma and Oien, Professor Karin and Anderson, Professor Kurt and Biankin, Professor Andrew and Timpson, Dr Paul and Carter, Mr Ross and McGhee, Dr Ewan and McGarry, Ms Lynn and Evans, Professor Jeff and Steele, Dr Colin and Morton, Professor Jen and Chang, Professor David and Karim, Ms Saadia and Sansom, Professor Owen
• Authors: Miller, B. W., Morton, J. P., Pinese, M., Saturno, G., Jamieson, N. B., McGhee, E., Timpson, P., Leach, J., McGarry, L., Shanks, E., Bailey, P., Chang, D., Oien, K., Karim, S., Au, A., Steele, C., Carter, C. R., McKay, C., Anderson, K., Evans, T. R. J., Marais, R., Springer, C., Biankin, A., Erler, J. T., and Sansom, O. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: EMBO Molecular Medicine
• Publisher: EMBO Press
• ISSN: 1757-4676
• ISSN (Online): 1757-4684
• Copyright Holders: Copyright © 2015 The Authors
• First Published: First published in EMBO Molecular Medicine
• Publisher Policy: Reproduced under a Creative Commons License