Endothelial-cell FAK targeting sensitizes tumours to DNA-damaging therapy
Open accessAbstract
Chemoresistance is a serious limitation of cancer treatment. Until recently, almost all the work done to study this limitation has been restricted to tumour cells. 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-κB 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.
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Complex components of the tumor microenvironment can significantly affect the growth and metastasis of cancer via mechanical and biochemical factors.
“Various studies have demonstrated that complex components can significantly affect the growth and metastasis of cancer via mechanical and biochemical factors113–116.”
From Tumor-on-a-chip: from bioinspired design to biomedical application (2021) · cites this paper as [115]
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Cites
Cancer: Principles and Practice of Oncology.
(1991) · Annals of Internal Medicine · doi:10.7326/0003-4819-114-9-819_4 · Cited by 8,524 · see citing works
NF-κB functions as a tumour promoter in inflammation-associated cancer
Pikarsky, E., Porat, R., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E., & Ben-Neriah, Y. (2004) · Nature · doi:10.1038/nature02924 · Cited by 2,295 · see citing works
Fisher, R. I., Gaynor, E. R., Dahlberg, S., Oken, M. M., Grogan, T. M., Mize, E. M., Glick, J. H., Coltman, C. A., & Miller, T. P. (1993) · New England Journal of Medicine · doi:10.1056/nejm199304083281404 · Cited by 2,148 · see citing works
Cancer: Principles and Practice of Oncology
Gunn, W. G. (1994) · JAMA · doi:10.1001/jama.1994.03510350091047 · Cited by 1,810 · see citing works
Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion
Straussman, R., Morikawa, T., Shee, K., Barzily-Rokni, M., Qian, Z. R., Du, J., Davis, A., Mongare, M. M., Gould, J., Frederick, D. T., et al. (2012) · Nature · doi:10.1038/nature11183 · Cited by 1,771 · see citing works
Integrin-regulated FAK–Src signaling in normal and cancer cells
Mitra, S. K., & Schlaepfer, D. D. (2006) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2006.08.011 · Cited by 1,591 · see citing works
NF‐κB and the link between inflammation and cancer
DiDonato, J. A., Mercurio, F., & Karin, M. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01099.x · Cited by 1,490 · see citing works
Inflammation meets cancer, with NF-κB as the matchmaker
Ben‐Neriah, Y., & Karin, M. (2011) · Nature Immunology · doi:10.1038/ni.2060 · Cited by 1,378 · see citing works
Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors
Wilson, T. R., Fridlyand, J., Yan, Y., Penuel, E., Burton, L., Chan, E., Peng, J., Lin, E., Wang, Y., Sosman, J., et al. (2012) · Nature · doi:10.1038/nature11249 · Cited by 1,134 · see citing works
A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis
Acharyya, S., Oskarsson, T., Vanharanta, S., Malladi, S., Kim, J., Morris, P. G., Manova-Todorova, K., Leversha, M., Hogg, N., Seshan, V. E., et al. (2012) · Cell · doi:10.1016/j.cell.2012.04.042 · Cited by 1,085 · see citing works
The diverse and complex roles of NF-κB subunits in cancer
Perkins, N. D. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3204 · Cited by 845 · see citing works
Self-citationSun, Y., Campisi, J., Higano, C., Beer, T. M., Porter, P., Coleman, I., True, L., & Nelson, P. S. (2012) · Nature Medicine · doi:10.1038/nm.2890 · Cited by 793 · see citing works
Nakasone, E. S., Askautrud, H. A., Kees, T., Park, J.-H., Plaks, V., Ewald, A. J., Fein, M. R., Rasch, M. G., Tan, Y.-X., Qiu, J., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.017 · Cited by 477 · see citing works
Hambardzumyan, D., Becher, O. J., Rosenblum, M. K., Pandolfi, P. P., Manova-Todorova, K. O., & Holland, E. C. (2008) · Genes & Development · doi:10.1101/gad.1627008 · Cited by 468 · see citing works
Lu, J., Ye, X., Fan, F., Xia, L., Bhattacharya, R., Bellister, S. A., Tozzi, F., Sceusi, E. L., Zhou, Y., Tachibana, I., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2012.12.021 · Cited by 444 · see citing works
DNA Damage-Mediated Induction of a Chemoresistant Niche
Gilbert, L. A., & Hemann, M. T. (2010) · Cell · doi:10.1016/j.cell.2010.09.043 · Cited by 428 · see citing works
Shibue, T., & Weinberg, R. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0904227106 · Cited by 365 · see citing works
Stokes, J. B., Adair, S. J., Slack‐Davis, J. K., Walters, D. M., Tilghman, R. W., Hershey, E. D., Lowrey, B. T., Thomas, K. S., Bouton, A. H., Hwang, R. F., et al. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0261 · Cited by 233 · see citing works
McLean, G. W., Komiyama, N. H., Serrels, B., Asano, H., Reynolds, L. E., Conti, F. J. A., Hodivala‐Dilke, K., METZGER, D., Chambon, P., Grant, S. G. N., et al. (2004) · Genes & Development · doi:10.1101/gad.316304 · Cited by 223 · see citing works
Self-citationp53- and Mdm2-Independent Repression of NF-κB Transactivation by the ARF Tumor Suppressor
Rocha, S., Campbell, K. J., & Perkins, N. D. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00223-5 · Cited by 189 · see citing works
Self-citationEndothelial FAK is required for tumour angiogenesis
Tavora, B., Batista, S., Reynolds, L. E., Jadeja, S., Robinson, S. D., Kostourou, V., Hart, I. R., Fruttiger, M., Parsons, M., & Hodivala‐Dilke, K. (2010) · EMBO Molecular Medicine · doi:10.1002/emmm.201000106 · Cited by 151 · see citing works
Self-citationNuclear-localized focal adhesion kinase regulates inflammatory VCAM-1 expression
Lim, S., Miller, N. L. G., Chen, X. L., Tancioni, I., Walsh, C. T., Lawson, C., Uryu, S. A., Weis, S. M., Cheresh, D. A., & Schlaepfer, D. D. (2012) · The Journal of Cell Biology · doi:10.1083/jcb.201109067 · Cited by 105 · see citing works
Focal adhesion kinase modulates activation of NF-κB by flow in endothelial cells
Petzold, T., Orr, A. W., Hahn, C. S., Jhaveri, K. A., Parsons, J. T., & Schwartz, M. A. (2009) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00226.2009 · Cited by 83 · see citing works
Funakoshi‐Tago, M., Sonoda, Y., Tanaka, S., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213115200 · Cited by 58 · see citing works
Primary Mouse Endothelial Cell Culture for Assays of Angiogenesis
Reynolds, L. E., & Hodivala‐Dilke, K. (2006) · Humana Press eBooks · doi:10.1385/1-59259-969-9:503 · Cited by 53 · see citing works
Self-citationHagemeister, F. C. (2002) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-002-0447-1 · Cited by 41 · see citing works
Zhang, H. M., Keledjian, K. M., Rao, J. N., Zou, T., Liu, L., Marasa, B. S., Wang, S. R., Ru, L. W., Strauch, E. D., & Wang, J. (2005) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00450.2005 · Cited by 40 · see citing works
Modeling therapy resistance in genetically engineered mouse cancer models
Rottenberg, S., & Jonkers, J. (2008) · Drug Resistance Updates · doi:10.1016/j.drup.2007.11.002 · Cited by 38 · see citing works
FAK activation is required for TNF‐α‐induced IL‐6 production in myoblasts
Tseng, W., Su, C., & Tang, C. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22047 · Cited by 34 · see citing works
Establishment of murine cell lines by constitutive and conditional immortalization
May, T., Mueller, P. P., Weich, H. A., et al. (2005) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2005.03.027 · Cited by 32 · see citing works
Nakamura, J., Shigematsu, S., Yamauchi, K., et al. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.07.123 · Cited by 11 · see citing works
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McGranahan, N., & Swanton, C. (2017) · Cell · doi:10.1016/j.cell.2017.01.018 · Cited by 2,840 · see citing works
FAK in cancer: mechanistic findings and clinical applications
Sulzmaier, F. J., Jean, C., & Schlaepfer, D. D. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3792 · Cited by 1,381 · see citing works
Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy
Jiang, H., Hegde, S., Knolhoff, B. L., Zhu, Y., Herndon, J. M., Meyer, M. A., Nywening, T. M., Hawkins, W. G., Shapiro, I. M., Weaver, D. T., et al. (2016) · Nature Medicine · doi:10.1038/nm.4123 · Cited by 1,060 · see citing works
Tumor Microenvironment and Differential Responses to Therapy
Hirata, E., & Sahai, E. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026781 · Cited by 422 · see citing works
Tumor-on-a-chip: from bioinspired design to biomedical application
Liu, X., Fang, J., Huang, S., Wu, X., Xie, X., Wang, J., Liu, F., Zhang, M., Peng, Z., & Hu, N. (2021) · Microsystems & Nanoengineering · doi:10.1038/s41378-021-00277-8 · Cited by 246 · see citing works
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Tapial Martínez, P., López Navajas, P., & Lietha, D. (2020) · Biomolecules · doi:10.3390/biom10020179 · Cited by 206 · see citing works
Bent, E. H., Gilbert, L. A., & Hemann, M. T. (2016) · Genes & Development · doi:10.1101/gad.284851.116 · Cited by 179 · see citing works
Applications of tumor chip technology
Hachey, S. J., & Hughes, C. C. W. (2018) · Lab on a Chip · doi:10.1039/c8lc00330k · Cited by 128 · see citing works
Lander, V. E., Belle, J. I., Kingston, N. L., Herndon, J. M., Hogg, G. D., Liu, X., Kang, L.-I., Knolhoff, B. L., Bogner, S. J., Baer, J. M., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0192 · Cited by 114 · see citing works
Tang, K.-J., Constanzo, J. D., Venkateswaran, N., Melegari, M., Ilcheva, M., Morales, J. C., Skoulidis, F., Heymach, J. V., Boothman, D. A., & Scaglioni, P. P. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2603 · Cited by 91 · see citing works
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Hooglugt, A., van der Stoel, M. M., Boon, R. A., & Huveneers, S. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2020.612802 · Cited by 82 · see citing works
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Yang, S., Han, G., Chen, Q., Yu, L., Wang, P., Zhang, Q., Dong, J., Zhang, W., & Huang, J. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s287523 · Cited by 81 · see citing works
The FAK inhibitor BI 853520 exerts anti-tumor effects in breast cancer
Tiede, S., Meyer-Schaller, N., Kalathur, R. K. R., Ivanek, R., Fagiani, E., Schmassmann, P., Stillhard, P., Häfliger, S., Kraut, N., Schweifer, N., et al. (2018) · Oncogenesis · doi:10.1038/s41389-018-0083-1 · Cited by 66 · see citing works
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- Authors
- Tavora, B., Reynolds, L. E., Batista, S., Demircioglu, F., Fernandez, I., Lechertier, T., Lees, D. M., Wong, P.-P., Alexopoulou, A., Elia, G., Clear, A., Ledoux, A., Hunter, J., Perkins, N., Gribben, J. G., & Hodivala-Dilke, K. M.
- Affiliations
- Queen Mary University of London (GB)
- Newcastle University (GB)
- ORCID
- Venue
- Nature
- Published
- 2014-07-27
- Volume
- 514
- Issue
- 7520
- Pages
- 112-116
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4533916
- OpenAlex
- W2121290668
- Cited by
- 163
- References
- 31
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 19 · 2023: 12 · 2022: 8 · 2021: 26 · 2020: 15 · 2019: 16 · 2018: 13 · 2017: 10 · 2016: 14 · 2015: 9 · 2014: 6
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Cancer Research UK (C9218/A12007, 12007)
- National Institutes of Health (4p01ca081534-16)
- Medical Research Council
- National Cancer Institute (P01CA095426, P01CA95426, P01-CA-081534)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- focal adhesion kinase, endothelial cells, tumor vasculature, chemosensitization, chemoresistance, radiotherapy, NF-κB activation, cytokine production, tumor microenvironment, doxorubicin, lymphoma
- MeSH terms
- Animals, Cell Nucleus, DNA Damage, Doxorubicin, Humans, Neoplasms, Phosphorylation, Cytokines, NF-kappa B, Apoptosis, Drug Resistance, Neoplasm, Active Transport, Cell Nucleus, Endothelial Cells, Cell Proliferation, Mice, Focal Adhesion Protein-Tyrosine Kinases
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