肉瘤样尿路上皮膀胱癌（SARC）是一种罕见且具有侵袭性的膀胱癌组织学亚型，其治疗选择有限且缺乏实验模型。在这里，我们报告了从 SARC 患者 (SarBC-01) 衍生的长期 3D 类器官模型的建立。 SarBC-01 模仿 SARC 的侵袭性形态、表型和转录特征，并在肉瘤样肿瘤中经常改变的基因（如 TP53 (p53) 和 RB1 (pRB)）中含有体细胞突变。高通量药物筛选使用包含 SarBC-01 和传统尿路上皮癌 (UroCa) 类器官中 1567 种化合物的库，确定了仅针对 SARC 细胞或仅针对 UroCa 细胞或两者都有活性的候选药物。其中，标准化疗药物抑制 SARC 和 UroCa 细胞，而一部分靶向药物对 SARC 细胞特别有效，包括针对糖皮质激素受体 (GR) 途径的药物。在两个独立的患者队列和类器官模型中，发现 GR 及其编码基因 NR3C1 在 SARC 中的表达显着高于 UroCa，这表明 GR 高表达是 SARC 肿瘤的标志。此外，糖皮质激素治疗损害了间充质形态，消除了 SARC 细胞的侵袭能力，并导致单细胞水平上与上皮间质转化逆转相关的转录组变化。总而言之，我们的研究强调了类器官在精准肿瘤学方面的力量，以及为驱动罕见肿瘤实体的因素提供关键见解的力量。© 2023。作者。

Sarcomatoid Urothelial Bladder Cancer (SARC) is a rare and aggressive histological subtype of bladder cancer for which therapeutic options are limited and experimental models are lacking. Here, we report the establishment of a long-term 3D organoid-like model derived from a SARC patient (SarBC-01). SarBC-01 emulates aggressive morphological, phenotypical, and transcriptional features of SARC and harbors somatic mutations in genes frequently altered in sarcomatoid tumors such as TP53 (p53) and RB1 (pRB). High-throughput drug screening, using a library comprising 1567 compounds in SarBC-01 and conventional urothelial carcinoma (UroCa) organoids, identified drug candidates active against SARC cells exclusively, or UroCa cells exclusively, or both. Among those, standard-of-care chemotherapeutic drugs inhibited both SARC and UroCa cells, while a subset of targeted drugs was specifically effective in SARC cells, including agents targeting the Glucocorticoid Receptor (GR) pathway. In two independent patient cohorts and in organoid models, GR and its encoding gene NR3C1 were found to be significantly more expressed in SARC as compared to UroCa, suggesting that high GR expression is a hallmark of SARC tumors. Further, glucocorticoid treatment impaired the mesenchymal morphology, abrogated the invasive ability of SARC cells, and led to transcriptomic changes associated with reversion of epithelial-to-mesenchymal transition, at single-cell level. Altogether, our study highlights the power of organoids for precision oncology and for providing key insights into factors driving rare tumor entities.© 2023. The Author(s).