Oncotarget

Research Papers:

Antibody-based targeting of alternatively spliced tissue factor: a new approach to impede the primary growth and spread of pancreatic ductal adenocarcinoma

Dusten Unruh, Betül Ünlü, Clayton S. Lewis, Xiaoyang Qi, Zhengtao Chu, Robert Sturm, Ryan Keil, Syed A. Ahmad, Timofey Sovershaev, Mariette Adam, Patrick Van Dreden, Barry J. Woodhams, Divya Ramchandani, Georg F. Weber, Janusz W. Rak, Alisa S. Wolberg, Nigel Mackman, Henri H. Versteeg and Vladimir Y. Bogdanov _

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Oncotarget. 2016; 7:25264-25275. https://doi.org/10.18632/oncotarget.7955

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Abstract

Dusten Unruh1, Betül Ünlü2, Clayton S. Lewis1, Xiaoyang Qi1, Zhengtao Chu1, Robert Sturm1, Ryan Keil1, Syed A. Ahmad1, Timofey Sovershaev3, Mariette Adam4, Patrick Van Dreden4, Barry J. Woodhams5, Divya Ramchandani6, Georg F. Weber6, Janusz W. Rak7, Alisa S. Wolberg8, Nigel Mackman8, Henri H. Versteeg2, Vladimir Y. Bogdanov1

1College of Medicine, University of Cincinnati, Cincinnati, OH, USA

2Leiden University Medical Center, Leiden, The Netherlands

3The Arctic University of Norway, Tromsø, Norway

4Diagnostica Stago R & D, Gennevilliers, France

5Haemacon Ltd, Bromley, UK

6College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA

7McGill University Health Centre, Montreal Children’s Hospital, Montreal, Canada

8University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Correspondence to:

Vladimir Y. Bogdanov, email: [email protected]

Keywords: pancreatic cancer, tissue factor, alternative splicing, β1 integrins, metastasis

Received: August 25, 2015     Accepted: February 13, 2016     Published: March 07, 2016

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.


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