Abstract
Organoid-based studies have revolutionized in vitro preclinical research and hold great promise for the cancer research field, including prostate cancer (PCa). However, experimental variability in organoid drug testing complicates reproducibility. For example, we observed PCa organoids to be less affected by cabazitaxel, abiraterone and enzalutamide as compared to corresponding single cells prior to organoid assembly. We hypothesized that three-dimensional (3D) organoid organization and the use of various 3D scaffolds impact treatment efficacy. Live-cell imaging of androgen-induced androgen receptor (AR) nuclear translocation and taxane-induced tubulin stabilization was used to investigate the impact of 3D scaffolds, spatial organoid distribution and organoid size on treatment effect. Scaffolds delayed AR translocation and tubulin stabilization, with Matrigel causing a more pronounced delay than synthetic hydrogel as well as incomplete tubulin stabilization. Drug effect was further attenuated the more centrally organoids were located in the scaffold dome. Moreover, cells in the organoid core revealed a delayed treatment effect compared to cells in the organoid periphery, underscoring the impact of organoid size. These findings indicate that analysis of organoid drug responses needs careful interpretation and requires dedicated read-outs with consideration of underlying technical aspects.
Highlights
In the last two decades, three-dimensional (3D) organoid culture techniques have been revolutionizing in vitro preclinical research [1]
Exposing assembled organoids to cabazitaxel elicited a significant shift in the dose-response curve compared to immediate exposure after seeding (p < 0.0001, Figure 1b), indicating a reduced cabazitaxel sensitivity due to the 3D organoid organization
The androgen receptor (AR)+ MSK-PCa2 organoid line was exposed to anti-androgen treatment directly after seeding of single cells or when organoids were established
Summary
In the last two decades, three-dimensional (3D) organoid culture techniques have been revolutionizing in vitro preclinical research [1]. A remarkable collection of epithelial organoids has been established from healthy, diseased and cancerous tissues, both of human and animal origin. These 3D organoids fill the experimental gap between cell lines and complex animal models, while accurately preserving patient-specific phenotypic and genetic characteristics [2,3,4]. Encouraging results from recent studies using patientderived tumor organoids for personalized drug response profiling highlight the exceptional potential of these near-patient preclinical models in oncology research [5,6,7,8]. In prostate cancer (PCa) research, organoids have been shown to be promising tools for preclinical drug testing and for studying emerging treatment resistant phenotypes [9,10,11,12,13,14,15,16]. 4.0/).
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