Journal
CELL DEATH AND DIFFERENTIATION
Volume 27, Issue 11, Pages 3037-3052Publisher
SPRINGERNATURE
DOI: 10.1038/s41418-020-0559-3
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Funding
- German Research Foundation [FOR2036 (MO 3226/1-1)]
- European Union's Horizon 2020 research and innovation program [675448]
- Cluster of Excellence in Simulation Technology [EXC 310/2]
- Marie Curie Actions (MSCA) [675448] Funding Source: Marie Curie Actions (MSCA)
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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.
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