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

Abstract

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.

• Authors: 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 W G Tait, Cathrin Hagenlocher, Nadine Pollak, Peter Scheurich, Markus Rehm
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 27 Issue 11 Pg. 3037-3052 (11 2020) ISSN: 1476-5403 [Electronic] England
• PMID: 32433558 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclooxygenase 2 Inhibitors
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• Celecoxib

Topics

• Apoptosis (drug effects)
• Celecoxib (pharmacology)
• Cell Line, Tumor
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Neoplasms (pathology)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (drug effects, metabolism)
• Spheroids, Cellular (drug effects, metabolism, pathology)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)