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.

中文翻译：

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应激诱导的 TRAILR2 表达克服了癌细胞球体中的 TRAIL 抗性。

3D 微环境对细胞凋亡敏感性的影响仍知之甚少。在这里，我们研究了生长至微转移大小的癌细胞球体对肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 的敏感性。有趣的是，在球状微环境中表现出明显的空间协调反应异质性：在由基因相同的细胞生长的球状体中，TRAIL 抗性亚群包围并保护 TRAIL 超敏细胞，从而增加整体治疗抵抗力。TRAIL 抗性层形成于增殖细胞和静止细胞的界面，缺乏 TRAILR1 和 TRAILR2 蛋白表达。相反，氧气和营养缺乏会促进内球体层 TRAIL 超敏细胞中 TRAILR2 的大量表达。COX-II 抑制剂塞来昔布进一步增强了球体中 TRAILR2 的表达，这可能是由于 ER 应激增加所致，从而使 TRAIL 抗性细胞层对治疗重新敏感。我们的分析解释了 TRAIL 反应异质性如何在明确的多细胞环境中表现出来，以及如何最小化和消除 TRAIL 抗性的空间障碍。