Department of Molecular Mechanisms of Disease, DMMD, University of Zürich, CH-8057 Zürich, Switzerland.
Molecular Life Science Program, Life Science Zürich Graduate School, University of Zürich, CH-8057 Zürich, Switzerland.
Proc Natl Acad Sci U S A. 2020 Feb 18;117(7):3637-3647. doi: 10.1073/pnas.1911673117. Epub 2020 Feb 5.
Prostate cancer (PCa) is the second leading cause of cancer death in men. Its clinical and molecular heterogeneities and the lack of in vitro models outline the complexity of PCa in the clinical and research settings. We established an in vitro mouse PCa model based on organoid technology that takes into account the cell of origin and the order of events. Primary PCa with deletion of the tumor suppressor gene (-del) can be modeled through down-regulation in mouse organoids. We used this system to elucidate the contribution of TIP5 in PCa initiation, a chromatin regulator that is implicated in aggressive PCa. High TIP5 expression correlates with primary -del PCa and this combination strongly associates with reduced prostate-specific antigen (PSA) recurrence-free survival. TIP5 is critical for the initiation of PCa of luminal origin mediated by -loss whereas it is dispensable once -loss mediated transformation is established. Cross-species analyses revealed a gene signature that identified a group of aggressive primary PCas characterized by -del, high-TIP5 expression, and a TIP5-regulated gene expression profile. The results highlight the modeling of PCa with organoids as a powerful tool to elucidate the role of genetic alterations found in recent studies in their time orders and cells of origin, thereby providing further optimization for tumor stratification to improve the clinical management of PCa.
前列腺癌（PCa）是男性癌症死亡的第二大主要原因。其临床和分子异质性以及缺乏体外模型突出了 PCa 在临床和研究环境中的复杂性。我们基于类器官技术建立了一种体外小鼠 PCa 模型，该模型考虑了细胞起源和事件的顺序。通过下调小鼠类器官中的肿瘤抑制基因缺失（-del）可以模拟原发性 PCa。我们使用该系统阐明了染色质调节剂 TIP5 在 PCa 起始中的作用，该调节剂与侵袭性 PCa 有关。高 TIP5 表达与原发性 -del PCa 相关，并且这种组合与前列腺特异性抗原（PSA）无复发生存率降低密切相关。TIP5 对于由 -loss 介导的管腔起源的 PCa 起始至关重要，而一旦 -loss 介导的转化建立，TIP5 就是可有可无的。种间分析揭示了一个基因特征，该特征鉴定了一组具有以下特征的侵袭性原发性 PCa：-del、高 TIP5 表达和 TIP5 调节的基因表达谱。结果强调了使用类器官对 PCa 进行建模，这是一种强大的工具，可以阐明最近研究中发现的遗传改变在其时间顺序和细胞起源中的作用，从而进一步优化肿瘤分层以改善 PCa 的临床管理。
