PT  - JOURNAL ARTICLE
AU  - Verena Waehle
AU  - Rosemarie Ungricht
AU  - Philipp S. Hoppe
AU  - Joerg Betschinger
TI  - Wilms Tumorigenesis in Human Kidney Organoids
AID  - 10.1101/2021.02.02.429313
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.02.02.429313
4099  - http://biorxiv.org/content/early/2021/02/02/2021.02.02.429313.short
4100  - http://biorxiv.org/content/early/2021/02/02/2021.02.02.429313.full
AB  - The loss or failure of cell differentiation is a hallmark of cancer, yet whether perturbation of differentiation is causal or consequential to malignant transformation is largely unclear. Wilms tumor is the most widespread kidney cancer in children. Here, we establish a model for Wilms tumorigenesis in human kidney organoids. We show that loss of the tumor suppressor WT1 during organoid formation induces overgrowth of kidney progenitor cells at the expense of differentiating 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. Genetic engineering of cancer lesions in human organoids therefore permits phenotypic modeling of tumor initiation and progression, and complements the current toolbox of pre-clinical Wilms tumor models.Competing Interest StatementThe authors have declared no competing interest.