title: Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy.
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 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.
authors.affiliation: Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK.
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Miller
authors.affiliation: Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Morton
authors.affiliation: The Garvan Institute of Medical Research, Sydney, NSW, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Pinese
authors.affiliation: Cancer Research UK Manchester Institute, Withington Manchester, UK.
authors.forename: Grazia
authors.initials: G
authors.lastname: Saturno
authors.affiliation: West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
authors.forename: Nigel B
authors.initials: NB
authors.lastname: Jamieson
authors.affiliation: Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK.
authors.forename: Ewan
authors.initials: E
authors.lastname: McGhee
authors.affiliation: The Garvan Institute of Medical Research, Sydney, NSW, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
authors.affiliation: Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK.
authors.forename: Joshua
authors.initials: J
authors.lastname: Leach
authors.affiliation: Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK.
authors.forename: Lynn
authors.initials: L
authors.lastname: McGarry
authors.affiliation: Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Shanks
authors.affiliation: Institute of Cancer Sciences University of Glasgow Garscube Estate, Glasgow, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Bailey
authors.affiliation: Institute of Cancer Sciences University of Glasgow Garscube Estate, Glasgow, UK.
authors.forename: David
authors.initials: D
authors.lastname: Chang
authors.affiliation: Institute of Cancer Sciences University of Glasgow Garscube Estate, Glasgow, UK.
authors.forename: Karin
authors.initials: K
authors.lastname: Oien
authors.affiliation: Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK.
authors.forename: Saadia
authors.initials: S
authors.lastname: Karim
authors.affiliation: Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Au
authors.affiliation: Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Steele
authors.affiliation: West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
authors.forename: Christopher Ross
authors.initials: CR
authors.lastname: Carter
authors.affiliation: West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: McKay
authors.affiliation: Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK.
authors.forename: Kurt
authors.initials: K
authors.lastname: Anderson
authors.affiliation: Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK Institute of Cancer Sciences University of Glasgow Garscube Estate, Glasgow, UK.
authors.forename: Thomas R Jeffry
authors.initials: TR
authors.lastname: Evans
authors.affiliation: Cancer Research UK Manchester Institute, Withington Manchester, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.affiliation: Institute of Cancer Research, London, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Springer
authors.affiliation: Institute of Cancer Sciences University of Glasgow Garscube Estate, Glasgow, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Biankin
authors.affiliation: Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen (UCPH), Denmark janine.erler@bric.ku.dk o.sansom@beatson.gla.ac.uk.
authors.forename: Janine T
authors.initials: JT
authors.lastname: Erler
authors.affiliation: Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK janine.erler@bric.ku.dk o.sansom@beatson.gla.ac.uk.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000473:pathology*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D000860:Hypoxia; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control; D010190:Pancreatic Neoplasms / Q000473:pathology*; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D008249:Protein-Lysine 6-Oxidase; D000093542:Gemcitabine
keywords: animal models of cancer; collagen cross‐linking; lysyl oxidase; pancreatic cancer