New Opportunities to Develop Preclinical Tools
Engineering Prostate Cancer from Induced Pluripotent Stem Cells-New Opportunities to Develop Preclinical Tools in Prostate and Prostate Cancer Studies - Beyond the Abstract
In a recently published review article, we described the advantages and disadvantages of current prostate cancer models and how the discovery of treatments for prostate cancer has been hindered by the lack of suitable and faithful in vitro models that recapitulate the full breadth of this heterogeneous disease. We also highlighted the opportunity for the development of new preclinical tools in the prostate research field and prostate cancer studies.
Prostate cancer is the most common cancer reported in men characterized by a malignant transformation of cells through the accumulation of molecular changes caused by genetic and epigenetic drivers. Prostate cancer growth is driven by androgens. One of the mainstays of treatment includes hormone therapy, which prevents testosterone from being produced or blocks its activity at the receptor level to inhibit tumor growth. However, the effects of hormone treatment can be bypassed as the tumor evolves and adapts to the treatment. Two main mechanisms are described, either by genetic changes in the androgen receptor (AR) and/or changes in transcription that lead to the production of alternative isoforms of AR. These molecular events allow cancer cells to bypass hormone treatment and leading to lethal castration-resistant prostate cancer. Prostate cancer tumors harbor driver mutations in specific genes such as TP53, PTEN, SPOP, FOXA1, CHD1, and TMPRSS2. The different combinations of these mutations are an indication of the complexity and the heterogeneity of this disease. In vitro approaches to study this biology would be greatly enhanced with additional models beyond cell lines, capable to recreate this heterogeneity.
Current in vitro tools used in prostate cancer research include two and three dimensional (2D, 3D) models. 2D models, such as prostate cancer cell lines and prostate primary cells can be cultured in a cost-effective manner but lack the structural complexity of in vivo tumors, marked by cell-cell and cell-extracellular matrix interactions. As regards to primary cells, they can also be difficult to obtain and establish in culture, often having a short lifespan. These models can also accumulate mutations due to selective pressures in prolonged culture time which can lead to genetic drift, becoming no longer representative of the tissues of origin. A recent publication revealed that there are large differences in transcriptomics data between cancer cell lines and their correspondent tumor samples, resulting in different genetic and chemical dependencies.2 The use of tissue slides, as an alternative approach to study prostate cancer, maintain tissue architecture but also present disadvantages such as rapidly deteriorating tissue quality ex vivo, compounding functional analyses. Other models such as animal xenografts and in vitro 3D organoids have been used in efforts to faithfully recreate the tumor ex vivo, overcoming the effects of 2D culture adaptations that deviate from the in situ phenotype. The use of animals to generate human patient-derived xenografts, however, is inefficient, expensive and the host’s system is physiologically incompatible to the human setting.
Patient-derived organoids are good alternatives to the models described above; however, they can only be reliably established from metastatic prostate cancer tumors and thus, can’t mimic other prostate cancer phenotypes. iPSC-derived prostate organoids have emerged as an alternative approach to overcome the issues described above. Human iPSCs can be grown efficiently and can be differentiated in a 3D manner to mimic the histology of prostate tissue, expressing definitive prostate markers. iPSC-derived prostate organoids can also reconstruct the patients’ genotype in real-time through the incorporation of different combinations of patient-specific driver mutations to generate avatars for drug testing that can be correlated to patient tissue biopsies. The generation of isogenic cells accordingly can also overcome the effect of genetic drift. In order to achieve these goals successfully, it is important to have a robust and validated iPSC-derived prostate organoid model.
In a recently published paper, we described the generation of iPSC-derived prostate organoids using an inductive co-culture method with rodent urogenital sinus mesenchyme cells (UGM). This differentiation protocol resulted in glandular structures that recapitulated prostate tissue histology and expressed key prostate markers such as AR, prostate-specific homeobox protein NKX3-1, and secretory prostate-specific antigen (PSA). This was a great advancement in the prostate research field, which can lead to drug discovery and insights into prostate development.
In summary, we discuss the advantages and limitations of current prostate models and in this review will provide insights for the development of a new preclinical prostate cancer model, using novel iPSC-derived prostate differentiation protocols.