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Endothelial-cell FAK targeting sensitizes tumours to DNA-damaging therapy

Lookup NU author(s): Dr Adeline Ledoux, Dr Jill Hunter, Professor Neil Perkins

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Abstract

Chemoresistance is a serious limitation of cancer treatment(1). Until recently, almost all the work done to study this limitation has been restricted to tumour cells(2). Here we identify a novel molecular mechanism by which endothelial cells regulate chemosensitivity. We establish that specific targeting of focal adhesion kinase (FAK; also known as PTK2) in endothelial cells is sufficient to induce tumour-cell sensitization to DNA-damaging therapies and thus inhibit tumour growth in mice. The clinical relevance of this work is supported by our observations that low blood vessel FAK expression is associated with complete remission in human lymphoma. Our study shows that deletion of FAK in endothelial cells has no apparent effect on blood vessel function per se, but induces increased apoptosis and decreased proliferation within perivascular tumour-cell compartments of doxorubicin-and radiotherapy-treated mice. Mechanistically, we demonstrate that endothelial-cell FAK is required for DNA-damage induced NF-kappa B activation in vivo and in vitro, and the production of cytokines from endothelial cells. Moreover, loss of endothelial-cell FAK reduces DNA-damage-induced cytokine production, thus enhancing chemosensitization of tumour cells to DNA-damaging therapies in vitro and in vivo. Overall, our data identify endothelial-cell FAK as a regulator of tumour chemosensitivity. Furthermore, we anticipate that this proof-of-principle data will be a starting point for the development of new possible strategies to regulate chemosensitization by targeting endothelial-cell FAK specifically.


Publication metadata

Author(s): Tavora B, Reynolds LE, Batista S, Demircioglu F, Fernandez I, Lechertier T, Lees DM, Wong PP, Alexopoulou A, Elia G, Clear A, Ledoux A, Hunter J, Perkins N, Gribben JG, Hodivala-Dilke KM

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2014

Volume: 514

Issue: 7520

Pages: 112-116

Print publication date: 02/10/2014

Online publication date: 27/07/2014

Acceptance date: 29/05/2014

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/nature13541

DOI: 10.1038/nature13541


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