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

前列腺癌（PCa）是男性中最常见的癌症，仅在英国每年就有超过47，000例新病例被诊断出来。它造成约12，000人死亡，每年使英国经济损失约1亿英镑。前列腺癌治疗方法的发现一直受到阻碍，因为在培养皿中缺乏易于处理和忠实的人类前列腺模型，这些模型概括了这种遗传异质性疾病的全部谱。因此，人们一直依赖于动物模型，这些模型可以被操纵来重建具有不同基因突变的癌症。人类诱导的多能干细胞（iPSC），胚胎样细胞，已经成为动物模型的一个令人信服的替代品，因为它们可以有效地生长，并且它们可以被处理以形成微型器官或类器官，我之前的工作有助于证明iPSC衍生的前列腺类器官，（“培养皿中的器官”）在实验室中忠实地模拟前列腺组织，为全世界的前列腺生物学家提供了强大的资源。我最近的工作表明，我们可以通过整合患者特有的遗传因素来重建患者独特的癌症生物学。这种强大的工具依赖于与啮齿动物细胞的诱导共培养方法，以诱导干细胞朝向前列腺命运-泌尿生殖间充质（UGM）细胞。虽然这种模型可以产生前列腺组织，但用定义的诱导分子取代啮齿动物细胞的更明确的协议将是一个重大的进步-挽救动物生命并提高世界各地研究人员对模型的可及性。我最近描述了驱动干细胞向前列腺谱系发展的UGM因子，并基于这一新的试点数据，我现在有机会开发一种新的干细胞衍生的人类类器官模型，不含动物组织。该模型将与大型国际科学界相关-包括研究（i）最常见的男性癌症，前列腺癌，（ii）良性前列腺增生（BPH），一种全球发生的男性年龄相关疾病，导致相当大的全球发病率（感染，泌尿系统症状和肾衰竭）和（iii）发育生物学家研究泌尿道疾病。我的国际调查，其中包括28个研究前列腺疾病的研究小组，证实了采用我的模型的热情，仅在我能够抽样的研究社区的一小部分中，就可能在5年内挽救大约13，250只动物的生命。通过这项重要的研究，我将取代使用动物产生hiPSC衍生的前列腺类器官，将这一模型的可及性扩大到世界各地没有动物设施的研究人员，并为许多其他人节省了无法负担的动物费用。这将有助于加速前列腺癌的研究。此外，这项工作将定义前列腺谱系的规范和监管程序的机制，并解决前列腺分化和成熟的分子景观。这将有助于阐明导致前列腺癌发生和进展期间关键发育程序重新唤醒的机制。这些分子事件的知识将通过发现新的治疗靶点和筛选对人类前列腺终点至关重要的药物来创造潜在的临床转化机会，这对于开发新的治疗方法至关重要。

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.