Modeling prostate cancer treatment responses in the organoid era: 3D environment impacts drug testing

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Organoid-based studies have revolutionized in vitro preclinical research and hold great promise for the cancer research field, including prostate cancer (PCa). However, experimental var-iability in organoid drug testing complicates reproducibility. For example, we observed PCa organ-oids 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 an-drogen-induced androgen receptor (AR) nuclear translocation and taxane-induced tubulin stabilization was used to investigate the impact of 3D scaffolds, spatial organoid distribution and organ-oid size on treatment effect. Scaffolds delayed AR translocation and tubulin stabilization, with Mat-rigel causing a more pronounced delay than synthetic hydrogel as well as incomplete tubulin sta-bilization. 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.

Original languageEnglish
Article number1572
Issue number11
Early online date22 Oct 2021
Publication statusPublished - Nov 2021

Bibliographical note

Funding Information:
This work was supported by the Translational Research Network for Prostate Cancer (TransPot) and was funded by the European Union?s Horizon 2020 research and innovation programme under the Marie Sk?odowska-Curie grant agreement No 721746. The Opera Phenix High Content Screening System within the Cancer Treatment Screening Facility is funded by the Daniel den Hoed Foundation.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


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