Developing a stem-cell prostate organoid model - reducing global animal usage in prostate development and cancer studies

Prostate cancer (PCa) is the most common cancer reported in men, with over 47,000 new cases diagnosed every year in the UK alone. It accounts for around 12,000 deaths and costs the UK economy around £100 million annually. The discovery of treatments for prostate cancer has been hindered by the lack of tractable and faithful human prostate models in the dish that recapitulate the full spectrum of this genetically heterogeneous disease. Accordingly, there has been a dependence on animal models that can be manipulated to recreate cancers with different gene mutations. Human-induced pluripotent stem cells (iPSCs), embryonic-like cells, have emerged as a compelling alternative to animal models, as they can be grown efficiently, and they can be treated to form mini-organs, or organoids, in vitro that can also be manipulated to generate the genetic diversity of prostate cancer biology.

My previous work helped to show that iPSC-derived prostate organoids ("organ in a dish") faithfully mimic prostate tissue in the lab providing a powerful resource to prostate biologists worldwide. My recent work has now shown we can reconstruct a patient's unique cancer biology by the incorporation of genetic elements specific to that patient. This powerful tool relies on an inductive co-culture method with rodent cells to induce stem cells towards a prostate fate - urogenital mesenchymal (UGM) cells. Although this model can produce prostatic tissue, a more defined protocol that replaces the rodent's cells with defined inductive molecules would be a major advance - saving animal lives and improving accessibility of the model to researchers worldwide.

I have recently characterised the UGM factors that drive stem cells towards a prostatic lineage and, based on this new pilot data, I have now the opportunity to develop a novel stem cell-derived human organoid model, free of animal tissue.

This model will be relevant to a large international scientific community - including those investigating (i) the commonest male cancer, prostate cancer, (ii) benign prostatic hyperplasia (BPH), a globally occurring male age-related disease causing considerable worldwide morbidity (infections, urinary symptoms and kidney failure) and (iii) developmental biologists looking at disorders of the urinary tract. My international survey, which included 28 research groups working on prostate disease, confirmed an enthusiasm to adopt my model, potentially saving approximately 13,250 animal lives over 5 years alone just in the fraction of the research community I was able to sample.

Through this important research, I will replace the use of animals in the generation of hiPSC-derived prostate organoids, expanding the accessibility of this model to researchers across the world without animal facilities and also by saving unaffordable animal costs for many others. This will help accelerate research into prostate cancer. Additionally, this work will define mechanisms of prostate-lineage specification and regulatory programmes and resolve the molecular landscape of prostate differentiation and maturation. This would help elucidate the mechanisms that lead to the reawakening of critical developmental programmes that occur during prostate cancer initiation and progression. The knowledge of such molecular events will create potential opportunities for clinical translation by the discovery of new therapeutic targets and the screening of pharmaceutical agents on human prostatic endpoints, essential for the development of new treatments.

BACKGROUND: Prostate cancer is the most common cancer in men, with over 47,000 new cases diagnosed every year in the UK alone. The discovery of treatments for prostate cancer has been hindered by the lack of clinically relevant human prostate models that recapitulate the full spectrum of this heterogeneous disease. Current in vitro tools, such as prostate cancer cell lines and prostate primary cells, lack the structural complexity of tumours. Other models such as animal xenografts have been used in efforts to recreate the tumour ex vivo, however these models are expensive, and the host's system is physiologically incompatible to the human setting.

OPPORTUNITY: My work has shown that human iPSC-derived prostate organoids mimic prostate tissue in vitro and they can also reconstruct the patient's cancer phenotype by the incorporation of mutations that promote the formation of prostate cancer. Our group was the first to establish a hiPSC-derived prostate organoid model using inductive urogenital mesenchymal (UGM) cells from rodents, which produces 3D layered structures faithfully resembling the human prostate and provides a new powerful tool for prostate studies. However, removing its dependence on animal tissue would be a huge advance.

AIM: I seek to develop a novel hiPSC-derived organoid model for prostate studies free of animal tissue.

PLAN: In order to establish prescribed factors, without the need for animal UGM, I recently undertook transcriptome sequencing of UGM cells to find which factors induce iPSCs towards a prostatic lineage fate. This pilot data, combined with previous work in human embryonic cells, has allowed me to design a novel animal-free differentiation protocol using hiPSCs.

Through this critical research, I will replace the use of animals by generating hiPSC-derived prostate organoids and reduce the use of animal models in the field of prostate cancer, expanding the accessibility of this model to researchers across the world.