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

TY - JOUR

T1 - Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly

T2 - inhibition of LOX abrogates metastasis and enhances drug efficacy

AU - Miller, Bryan W

AU - Morton, Jennifer P

AU - Pinese, Mark

AU - Saturno, Grazia

AU - Jamieson, Nigel B

AU - McGhee, Ewan

AU - Timpson, Paul

AU - Leach, Joshua

AU - McGarry, Lynn

AU - Shanks, Emma

AU - Bailey, Peter

AU - Chang, David

AU - Oien, Karin

AU - Karim, Saadia

AU - Au, Amy

AU - Steele, Colin

AU - Carter, Christopher Ross

AU - McKay, Colin

AU - Anderson, Kurt

AU - Evans, Thomas R Jeffry

AU - Marais, Richard

AU - Springer, Caroline

AU - Biankin, Andrew

AU - Erler, Janine T

AU - Sansom, Owen J

N1 - © 2015 Cancer Research UK Beatson Institute. Published under the terms of the CC BY 4.0 license.

PY - 2015/8/1

Y1 - 2015/8/1

N2 - 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 Kras(G12D/+) Trp53(R172H/+) (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.

AB - 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 Kras(G12D/+) Trp53(R172H/+) (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.

U2 - 10.15252/emmm.201404827

DO - 10.15252/emmm.201404827

M3 - Journal article

C2 - 26077591

SN - 1757-4676

VL - 7

SP - 1063

EP - 1076

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 8

ER -