The tumor suppressor WT1 drives progenitor cell progression and epithelialization to prevent Wilms tumorigenesis in human kidney organoids.
Cell Line, Tumor
Cell Transformation, Neoplastic
/ genetics
Computational Biology
/ methods
Gene Deletion
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Genes, Tumor Suppressor
Humans
Hyperplasia
Immunophenotyping
Kidney Neoplasms
/ etiology
Molecular Sequence Annotation
Neoplastic Stem Cells
/ metabolism
Organoids
/ metabolism
WT1 Proteins
/ genetics
Wilms Tumor
/ etiology
SIX2
WT1
Wilms tumor
disease modeling
human kidney organoid
iPS cell
kidney progenitor cell
mesenchymal-epithelial transition
pediatric tumor
tumor suppressor
Journal
Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300
Informations de publication
Date de publication:
14 09 2021
14 09 2021
Historique:
received:
18
02
2021
revised:
30
07
2021
accepted:
30
07
2021
pubmed:
28
8
2021
medline:
11
3
2022
entrez:
27
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34450039
pii: S2213-6711(21)00389-1
doi: 10.1016/j.stemcr.2021.07.023
pmc: PMC8452534
pii:
doi:
Substances chimiques
WT1 Proteins
0
WT1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2107-2117Informations de copyright
Copyright © 2021 Friedrich Miescher Institute for Biomedical Research. Published by Elsevier Inc. All rights reserved.
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