Modeling prostate cancer using patient-derived organoids and cell lines : implications for Personalized Medicine

Abstract

Background: In Lebanon, Prostate cancer (PCa) is the one of the most commonly diagnosed malignancy in men. It is a heterogeneous disease associated with large-scale genomic rearrangements and extensive copy number alterations involving multiple chromosomes. The currently available cancer models fail to recapitulate the progression of PCa, its metastasis, and its progression to castration-resistant states. The epithelial-mesenchymal transition (EMT), marks a key step in the invasion and malignant progression of PCa, and plays a substantial role in therapeutic resistance to antiandrogens and radiotherapy. Therefore, the identification of the onset of metastatic dissemination through assessment of molecular markers of EMT is highly needed to further aid in the development of a novel system for predicting the prognosis of PCa. In addition, the three-dimensional (3D) organoid culture systems are rapidly emerging as potential models to investigate both basic developmental processes and disease mechanisms, where patient-derived organoids have demonstrated the ability to mimic genetically and phenotypically the tumor of origin. Objective: The overall aim of this thesis is to establish novel models to elucidate the mechanisms of PCa progression. Our first aim was to demonstrate that EMT status can model the progression status of the disease and predict the prognosis-recurrence. Our second aim was to employ fresh tissue specimens from a treatment-naïve cohort to establish 3D patient-derived organoids as an in vitro disease model for PCa progression and drug response. The third aim was to optimize the previously established extensive organoids culture system in the attempt to increase the formation efficiency and reduce the costly requirements. Knowing the difficulty in establishing primary PCa cell lines, our last aim was to generate novel PCa patient-derived cell lines. Methods: For the first aim, a total of 122 radical prostatectomy (RP) specimens from patients with locally-advanced PCa were analyzed. Sections we