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Decoy receptors block TRAIL sensitivity at a supracellular level: the role of stromal cells in controlling tumour TRAIL sensitivity

Oncogene volume 35, pages 1261–1270 (2016)Cite this article

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Abstract

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand cytokine known for its cytotoxic activity against malignantly transformed cells. TRAIL induces cell death through binding to death receptors DR4 and DR5. The inhibitory decoy receptors (DcR1 and DcR2) co-expressed with death receptor 4 (DR4)/DR5 on the same cell can block the transmission of the apoptotic signal. Here, we show that DcRs also regulate TRAIL sensitivity at a supracellular level and thus represent a mechanism by which the microenvironment can diminish tumour TRAIL sensitivity. Mathematical modelling and layered or spheroid stroma–extracellular matrix–tumour cultures were used to model the tumour microenvironment. By engineering TRAIL to escape binding by DcRs, we found that DcRs do not only act in a cell-autonomous or cis-regulatory manner, but also exert trans-cellular regulation originating from stromal cells and affect tumour cells, highlighting the potent inhibitory effect of DcRs in the tumour tissue and the necessity of selective targeting of the two death-inducing TRAIL receptors to maximise efficacy.

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Acknowledgements

We thank Teresa McHale (University College Hospital, Galway) for scoring the tissue microarrays and Paul Lohan for immunohistochemical assistance. We acknowledge the facilities and scientific and technical assistance of the Centre for Microscopy and Imaging at National University of Ireland, Galway (NUIG), a facility that is funded by NUIG and the Irish Government’s Programme for Research in Third Level Institutions, Cycles 4 and 5, National Development Plan. AMS was partially supported by a Juan de la Cierva grant of the Spanish ministry of Science and Education. Financial Support: The project was funded by Enterprise Ireland, National Development Plan of Ireland, Commercialisation Fund to AS and ES (CFTD/06/112), SFI SIRG award to ES (09/SIRG /B1575) and Millennium Grant to ES from the NUIG.

Author information

Author notes

  1. L O'Leary

    Present address: 9Present address: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.,

  2. C R Reis

    Present address: 10Present address: Department of Cell Biology, University of Texas Southwestern Medical Centre, Dallas, TX 75390-9039, USA.,

  3. P Correa de Sampaio

    Present address: 11Present address: Department of Cancer Biology, Metastasis Research Centre, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,

Authors and Affiliations

  1. Apoptosis Research Centre, National University of Ireland, Galway, Ireland

    L O'Leary, S Deegan, S P S Dhami, A Samali & E Szegezdi

  2. EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona, Spain,

    A M van der Sloot & L Serrano

  3. Institute for Research in Immunology and Cancer, University of Montreal, 2950, Chemin de Polytechnique Pavillon Marcelle-Coutu, Dock 20, Montréal, Québec, Canada

    A M van der Sloot

  4. Department of Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands

    C R Reis, R H Cool & W J Quax

  5. Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland

    A E Ryan

  6. National Centre for Biomedical Engineering Science, National University of Ireland,, Galway, Ireland

    L S Murillo

  7. Department of Oncology, University of Cambridge, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK

    P Correa de Sampaio & G Murphy

  8. Centre for Microscopy and Imaging, National University of Ireland,, Galway, Ireland

    K Thompson

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Correspondence to A Samali or E Szegezdi.

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A Samali is a scientific founding member and Director of Aquila Ltd.

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O'Leary, L., van der Sloot, A., Reis, C. et al. Decoy receptors block TRAIL sensitivity at a supracellular level: the role of stromal cells in controlling tumour TRAIL sensitivity. Oncogene 35, 1261–1270 (2016). https://doi.org/10.1038/onc.2015.180

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