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Wilms Tumorigenesis in Human Kidney Organoids

Verena Waehle, Rosemarie Ungricht, Philipp S. Hoppe, Joerg Betschinger
doi: https://doi.org/10.1101/2021.02.02.429313
Verena Waehle
1Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel
2Faculty of Sciences, University of Basel, CH-4003 Basel
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Rosemarie Ungricht
3Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel
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Philipp S. Hoppe
3Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel
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Joerg Betschinger
1Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel
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  • For correspondence: joerg.betschinger@fmi.ch
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SUMMARY

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 Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 02, 2021.
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Wilms Tumorigenesis in Human Kidney Organoids
Verena Waehle, Rosemarie Ungricht, Philipp S. Hoppe, Joerg Betschinger
bioRxiv 2021.02.02.429313; doi: https://doi.org/10.1101/2021.02.02.429313
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Wilms Tumorigenesis in Human Kidney Organoids
Verena Waehle, Rosemarie Ungricht, Philipp S. Hoppe, Joerg Betschinger
bioRxiv 2021.02.02.429313; doi: https://doi.org/10.1101/2021.02.02.429313

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