Organoids: An Emerging Precision Medicine Model for Prostate Cancer Research

Abstract

Prostate cancer (PCa) has been known as the most prevalent cancer disease and the second leading cause of cancer mortality in men almost all over the globe. There is an urgent need for establishment of PCa models that can recapitulate the progress of genomic landscapes and molecular alterations during development and progression of this disease. Notably, several organoid models have been developed for assessing the complex interaction between PCa and its surrounding microenvironment. In recent years, PCa organoids have been emerged as powerful in vitro 3D model systems that recapitulate the molecular features (such as genomic/epigenomic changes and tumor microenvironment) of PCa metastatic tumors. In addition, application of organoid technology in mechanistic studies (i.e., for understanding cellular/subcellular and molecular alterations) and translational medicine has been recognized as a promising approach for facilitating the development of potential biomarkers and novel therapeutic strategies. In this review, we summarize the application of PCa organoids in the high-throughput screening and establishment of relevant xenografts for developing novel therapeutics for metastatic, castration resistant, and neuroendocrine PCa. These organoid-based studies are expected to expand our knowledge from basic research to clinical applications for PCa diseases. Furthermore, we also highlight the optimization of PCa cultures and establishment of promising 3D organoid models for in vitro and in vivo investigations, ultimately facilitating mechanistic studies and development of novel clinical diagnosis/prognosis and therapies for PCa.

Keywords: 3D model; castration resistant prostate cancer (CRPC); in vitro and in vivo models; neuroendocrine prostate cancer (NEPC); organoids; precision medicine; prostate cancer.

Figure 1

Development of PCa organoids. (1) PCa organoids can be generated from tissues and blood samples of PCa patients. The PCa tissues and blood samples cultured in Matrigel-containing medium are eventually formed 3D PCa organoids (procedures are indicated by the blue arrows). (2) Organoids can be developed from embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and patient-derived adult stem cells from both normal and cancerous tissues (ASCs). These ESC and iPSC cells can be cultured in Matrigel-containing medium and formed normal prostate organoids. After multiple genetic mutations/modifications, onco-mutations, and/or exposures to genotoxicity, these non-tumor organoids have the opportunity to be developed into PCa organoids (procedure indicated by solid black arrows).

Figure 2

The majority of PCas are defined by abnormal luminal cell development and lack of basal cells when compared to prostate tissues with normal basal and luminal cells. During transformation to neoplasm, impairment of prostatic epithelium was characterized. The normal prostatic cluster of cells (normal prostate organoid, Left) consists of an epithelial compartment comprising of basal (sky blue) and luminal (light orange) cells, and a limited population of neuroendocrine cells that act as stem cells in response to repairing the cellular damage. During neoplastic progression, a normal prostate organoid is transformed into a PCa organoid through multiple genetic alterations and onco-mutations. We note that a PCa organoid (Right) is characterized by luminal hyperproliferation, breakdown of basement membrane, loss of basal cells, prominent nucleoli (blue/pink), and nuclear enlargement.

Figure 3

The summarized picture of a differential PCa culture from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) transformed after the carcinogenesis process, mouse PCa, cell line-derived xenograft (CDX) or patient-derived xenograft (PDX) from mice, and tissue or circulating tumor cells of a PCa patient. PCa cells and/or tissues are also developed for a monolayer (2D) cell culture model and are subject to be developed to 3D organoid cultures. PCa representative organoids can be utilized for different applications including genomics, toxicology, gene editing, drug development and personalized medicine.