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

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journal contribution
posted on 2021-01-07, 17:18 authored by Daniela Stöhr, Jens O Schmid, Tobias B Beigl, Alexandra Mack, Daniela S Maichl, Kai Cao, Beate Budai, Gavin Fullstone, Roland E Kontermann, Thomas E Mürdter, Stephen WG Tait, Cathrin Hagenlocher, Nadine Pollak, Peter Scheurich, Markus RehmMarkus Rehm
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.


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Associated research data files

Supplementary material available at https://doi.org/10.1038/s41418-020-0559-3


The original article is available at https://www.nature.com/

Published Citation

Stöhr D, Schmid JO, Beigl TB, Mack A, Maichl DS, Cao K, Budai B, Fullstone G, Kontermann RE, Mürdter TE, Tait SWG, Hagenlocher C, Pollak N, Scheurich P, Rehm M. Stress-induced TRAILR2 expression overcomes TRAIL resistance in cancer cell spheroids. Cell Death & Differentiation. 2020;27(11):3037-3052.

Publication Date

20 May 2020

PubMed ID



  • Centre for Systems Medicine
  • Physiology and Medical Physics

Research Area

  • Cancer


Springer Nature


  • Published Version (Version of Record)