Prostate Cancer and the DNA Damage Response: Models and Mechanisms

This thesis first describes the development and application of 3D in vitro PCa models: tissue slices culture and organoids culture. These 3D platform for PCa defined in this thesis may be helpful to standardize ex vivo culturing of patient material and shows the promising future of personalized medicine in PCa treatment. Next, the abundance and RNA content of EVs secreted from tissue slices in culture medium were analyzed, showing that EVs may reflect the biological effects on the original cells in the tumor slice and that this may yield reliable markers for monitoring treatment response over time in the same tumor slice. Lastly, using PCa progression cell model and tissue slices model, we demonstrate that AR suppression treatments can act as a radiosensitizer in both AR-expressing preclinical PCa models and the mechanism of action causing this radiosensitization involves regulation of the NHEJ DNA repair. The studies in this thesis provide new strategies for generation of novel 3D in vitro PCa model and broaden our understanding of DDR defects and AR-DDR interplay in PCa, this knowledge can be used to improve diagnostic, prognostic and therapeutic approaches for PCa management.

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