Waehle, Verena, Ungricht, Rosemarie, Hoppe, Philipp and Betschinger, Joerg (2021) The tumor suppressor WT1 drives progenitor cell progression and epithelialization to prevent Wilms tumorigenesis in human kidney organoids. Stem cell reports, 16. pp. 1-11. ISSN 2213-6711

Abstract

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.

Item Type:	Article
Date Deposited:	15 Sep 2021 00:45
Last Modified:	15 Sep 2021 00:45
URI:	https://oak.novartis.com/id/eprint/44135