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Updated: Dec 21, 2025
Establishing 3-Dimensional Spheroids from Patient-Derived Tumor Samples and Evaluating their Sensitivity to Drugs
Published on: December 16, 2022
Stress-induced TRAILR2 expression overcomes TRAIL resistance in cancer cell spheroids
Daniela Stöhr1, Jens O Schmid2,3, Tobias B Beigl1
1Institute of Cell Biology and Immunology, University of Stuttgart, 70569, Stuttgart, Germany.
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.
Insights
Cancer cell spheroids show varied responses to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL-resistant cells protect sensitive cells, increasing treatment resistance, but this can be overcome.
Area of Science:
- Cell Biology
- Cancer Research
- Biophysics
Background:
- The 3D microenvironment's role in cancer cell apoptosis is not fully understood.
- Cancer cell spheroids mimic micrometastases, offering a model to study treatment resistance.
Purpose of the Study:
- To investigate how 3D microenvironments influence cancer cell susceptibility to TRAIL.
- To understand the spatial distribution and mechanisms of TRAIL resistance in spheroids.
Main Methods:
- Culturing cancer cell spheroids to mimic micrometastastases.
- Analyzing spatial variations in cell populations and protein expression (TRAILR1, TRAILR2).
- Investigating the effect of oxygen/nutrient levels and celecoxib on TRAIL sensitivity.
Main Results:
- TRAIL-resistant subpopulations within spheroids protect TRAIL-hypersensitive cells, increasing overall resistance.
- TRAIL resistance is linked to cell proliferation status and low TRAIL receptor expression.
- Inner spheroid layers show high TRAILR2 expression due to hypoxia and nutrient deprivation.
- Celecoxib enhances TRAILR2 expression and re-sensitizes resistant cells.
Conclusions:
- Spatially organized heterogeneities in TRAIL response are key to spheroid treatment resistance.
- Understanding these spatial barriers is crucial for developing effective cancer therapies.
- Targeting receptor expression and microenvironmental factors can overcome TRAIL resistance.
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