Wilms tumor is the most widespread kidney cancer in children and frequently associated with homozygous loss of the tumor suppressor WT1. Pediatric tumorigenesis is largely inaccessible in humans. Here, we develop a human kidney organoid model for Wilms tumor formation and show that deletion of WT1 during organoid development induces overgrowth of kidney progenitor cells at the expense of differentiating glomeruli and tubules. Functional and gene expression analyses demonstrate that absence of WT1 halts progenitor cell progression at a pre-epithelialized cell state and recapitulates the transcriptional changes detected in a subgroup of Wilms tumor patients with ectopic myogenesis. By “transplanting” WT1 mutant cells into wild-type kidney organoids, we find that their propagation requires an untransformed microenvironment. This work defines the role of WT1 in kidney progenitor cell progression and tumor suppression, and establishes human kidney organoids as a phenotypic model for pediatric tumorigenesis.

肾母细胞瘤是儿童中最常见的肾癌，通常与肿瘤抑制因子WT1的纯合性缺失有关。儿童肿瘤的发生在人类中基本上是难以实现的。在这里，我们开发了用于肾母细胞瘤形成的人类肾脏类器官模型，并表明在类器官发育过程中删除WT1会诱导肾脏祖细胞过度生长，但会损害肾小球和肾小管的分化。功能和基因表达分析表明， WT1的缺失使祖细胞进展停止在上皮前细胞状态，并概括了在患有异位肌生成的肾母细胞瘤患者亚组中检测到的转录变化。通过将WT1突变细胞“移植”到野生型肾类器官中，我们发现它们的繁殖需要未转化的微环境。这项工作定义了 WT1 在肾祖细胞进展和肿瘤抑制中的作用，并建立了人肾类器官作为儿科肿瘤发生的表型模型。