Stress-induced TRAILR2 expression overcomes TRAIL resistance in cancer cell spheroids

Stöhr, D. et al. (2020) Stress-induced TRAILR2 expression overcomes TRAIL resistance in cancer cell spheroids. Cell Death and Differentiation, 27(11), pp. 3037-3052. (doi: 10.1038/s41418-020-0559-3) (PMID:32433558) (PMCID:PMC7560834)

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The influence of 3D microenvironments on apoptosis susceptibility remains poorly understood. Here, we studied the susceptibility of cancer cell spheroids, grown to the size of micrometastases, to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Interestingly, pronounced, spatially coordinated response heterogeneities manifest within spheroidal microenvironments: In spheroids grown from genetically identical cells, TRAIL-resistant subpopulations enclose, and protect TRAIL-hypersensitive cells, thereby increasing overall treatment resistance. TRAIL-resistant layers form at the interface of proliferating and quiescent cells and lack both TRAILR1 and TRAILR2 protein expression. In contrast, oxygen, and nutrient deprivation promote high amounts of TRAILR2 expression in TRAIL-hypersensitive cells in inner spheroid layers. COX-II inhibitor celecoxib further enhanced TRAILR2 expression in spheroids, likely resulting from increased ER stress, and thereby re-sensitized TRAIL-resistant cell layers to treatment. Our analyses explain how TRAIL response heterogeneities manifest within well-defined multicellular environments, and how spatial barriers of TRAIL resistance can be minimized and eliminated.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Tait, Professor Stephen and Cao, Dr Kai
Authors: Stöhr, D., Schmid, J. O., Beigl, T. B., Mack, A., Maichl, D. S., Cao, K., Budai, B., Fullstone, G., Kontermann, R. E., Mürdter, T. E., Tait, S. W.G., Hagenlocher, C., Pollak, N., Scheurich, P., and Rehm, M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cell Death and Differentiation
Publisher:Springer Nature
ISSN (Online):1476-5403
Published Online:20 May 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published Cell Death and Differentiation 27(11): 3037-3052
Publisher Policy:Reproduced under a Creative Commons license

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