title: Decoy receptors block TRAIL sensitivity at a supracellular level: the role of stromal cells in controlling tumour TRAIL sensitivity.
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.
authors.affiliation: Apoptosis Research Centre, National University of Ireland, Galway, Ireland.
authors.forename: L
authors.initials: L
authors.lastname: O'Leary
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona, Spain.|Institute for Research in Immunology and Cancer, University of Montreal, 2950, Chemin de Polytechnique Pavillon Marcelle-Coutu, Dock 20, Montréal, Québec, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: van der Sloot
authors.affiliation: Department of Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: C R
authors.initials: CR
authors.lastname: Reis
authors.affiliation: Apoptosis Research Centre, National University of Ireland, Galway, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: Deegan
authors.affiliation: Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland.
authors.forename: A E
authors.initials: AE
authors.lastname: Ryan
authors.affiliation: Apoptosis Research Centre, National University of Ireland, Galway, Ireland.
authors.forename: S P S
authors.initials: SP
authors.lastname: Dhami
authors.affiliation: National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland.
authors.forename: L S
authors.initials: LS
authors.lastname: Murillo
authors.affiliation: Department of Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: R H
authors.initials: RH
authors.lastname: Cool
authors.affiliation: Department of Oncology, University of Cambridge, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
authors.forename: P
authors.initials: P
authors.lastname: Correa de Sampaio
authors.affiliation: Centre for Microscopy and Imaging, National University of Ireland, Galway, Ireland.
authors.forename: K
authors.initials: K
authors.lastname: Thompson
authors.affiliation: Department of Oncology, University of Cambridge, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
authors.forename: G
authors.initials: G
authors.lastname: Murphy
authors.affiliation: Department of Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: W J
authors.initials: WJ
authors.lastname: Quax
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Serrano
authors.affiliation: Apoptosis Research Centre, National University of Ireland, Galway, Ireland.
authors.forename: A
authors.identifier: http://orcid.org/0000-0002-8610-8375
authors.initials: A
authors.lastname: Samali
authors.affiliation: Apoptosis Research Centre, National University of Ireland, Galway, Ireland.
authors.forename: E
authors.initials: E
authors.lastname: Szegezdi
mesh_terms: D045744:Cell Line, Tumor; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011487:Protein Conformation; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D053320:Receptors, Tumor Necrosis Factor, Member 10c / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics / Q000378:metabolism*
chemical_list: D058851:GPI-Linked Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; C108661:TNFRSF10C protein, human; C451501:TNFRSF10D protein, human; D053319:Tumor Necrosis Factor Decoy Receptors