title: Antibody-based targeting of alternatively spliced tissue factor: a new approach to impede the primary growth and spread of pancreatic ductal adenocarcinoma.
abstract: Alternatively spliced Tissue Factor (asTF) is a secreted form of Tissue Factor (TF), the trigger of blood coagulation whose expression levels are heightened in several forms of solid cancer, including pancreatic ductal adenocarcinoma (PDAC). asTF binds to β1 integrins on PDAC cells, whereby it promotes tumor growth, metastatic spread, and monocyte recruitment to the stroma. In this study, we determined if targeting asTF in PDAC would significantly impact tumor progression. We here report that a novel inhibitory anti-asTF monoclonal antibody curtails experimental PDAC progression. Moreover, we show that tumor-derived asTF is able to promote PDAC primary growth and spread during early as well as later stages of the disease. This raises the likelihood that asTF may comprise a viable target in early- and late-stage PDAC. In addition, we show that TF expressed by host cells plays a significant role in PDAC spread. Together, our data demonstrate that targeting asTF in PDAC is a novel strategy to stem PDAC progression and spread.
authors.affiliation: College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Dusten
authors.initials: D
authors.lastname: Unruh
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Betül
authors.initials: B
authors.lastname: Ünlü
authors.affiliation: College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Clayton S
authors.initials: CS
authors.lastname: Lewis
authors.affiliation: College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Qi
authors.affiliation: College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Chu
authors.affiliation: College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Sturm
authors.affiliation: College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Keil
authors.affiliation: College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Syed A
authors.initials: SA
authors.lastname: Ahmad
authors.affiliation: The Arctic University of Norway, Tromsø, Norway.
authors.forename: Timofey
authors.initials: T
authors.lastname: Sovershaev
authors.affiliation: Diagnostica Stago R & D, Gennevilliers, France.
authors.forename: Mariette
authors.initials: M
authors.lastname: Adam
authors.affiliation: Diagnostica Stago R & D, Gennevilliers, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Van Dreden
authors.affiliation: Haemacon Ltd, Bromley, UK.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Woodhams
authors.affiliation: College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Ramchandani
authors.affiliation: College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Weber
authors.affiliation: McGill University Health Centre, Montreal Children's Hospital, Montreal, Canada.
authors.forename: Janusz W
authors.initials: JW
authors.lastname: Rak
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Alisa S
authors.initials: AS
authors.lastname: Wolberg
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Henri H
authors.initials: HH
authors.lastname: Versteeg
authors.affiliation: College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Vladimir Y
authors.initials: VY
authors.lastname: Bogdanov
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000473:pathology*; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D013925:Thromboplastin
keywords: alternative splicing; metastasis; pancreatic cancer; tissue factor; β1 integrins