Nephron Progenitor But Not Stromal Progenitor Cells Give Rise to Wilms Tumors in Mouse Models with β-Catenin Activation or Wt1 Ablation and Igf2 Upregulation

Abstract

Wilms tumor, a common childhood tumor of the kidney, is thought to arise from undifferentiated renal mesenchyme. Variable tumor histology and the identification of tumor subsets displaying different gene expression profiles suggest that tumors may arise at different stages of mesenchyme differentiation and that this ontogenic variability impacts tumor pathology, biology, and clinical outcome. To test the tumorigenic potential of different cell types in the developing kidney, we used kidney progenitor-specific Cre recombinase alleles to introduce Wt1 and Ctnnb1 mutations, two alterations observed in Wilms tumor, into embryonic mouse kidney, with and without biallelic Igf2 expression, another alteration that is observed in a majority of tumors. Use of a Cre allele that targets nephron progenitors to introduce a Ctnnb1 mutation that stabilizes β-catenin resulted in the development of tumors with a predominant epithelial histology and a gene expression profile in which genes characteristic of early renal mesenchyme were not expressed. Nephron progenitors with Wt1 ablation and Igf2 biallelic expression were also tumorigenic but displayed a more triphasic histology and expressed early metanephric mesenchyme genes. In contrast, the targeting of these genetic alterations to stromal progenitors did not result in tumors. These data demonstrate that committed nephron progenitors can give rise to Wilms tumors and that committed stromal progenitors are less tumorigenic, suggesting that human Wilms tumors that display a predominantly stromal histology arise from mesenchyme before commitment to a stromal lineage.

Platforms of in vivo genome editing with inducible Cas9 for advanced cancer modeling

“…To test whether the RC platform is practical for modeling cancer with complex genomic abnormalities, we first tried to recapitulate a previously reported Wilms’ tumor model with the activating mutation at Ctnnb1 in conjunction with the inactivating mutation at Wt1 . In the previous study, Ctnnb1 exon 3 was deleted by the conventional Cre/loxP system, which led to accumulation of the dominant stable form of β‐catenin protein .…”

Pharmacologic Inhibition of β-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor

“…23–25 Tumor growth and metastatic progression is accelerated by coordinate activation of Ras which is associated with increased β-catenin activation. 23 This suggests that β-catenin plays an important role in WT progression.…”

“…15 We and others have shown that such an activating mutation of β-catenin ( Ctnnb1 ) is sufficient to induce renal epithelial tumors that resemble human WT. 23–25 We have shown that coordinate activation of Ras with β-catenin leads to rapidly progressive, metastatic tumors that demonstrate markedly increased canonical β-catenin pathway activation. 23,24 In large series, similar activation has been demonstrated in the majority of human WT.…”

Overgrowth syndromes and pediatric cancers: how many roads lead to IGF2?

“…Furthermore, increased expression of IGF2 through these mechanisms is commonly found as a somatic event in Wilms tumors. Work with animal models has provided evidence that increased IGF2 expression is an important contributing factor in both BWS and Wilms tumor (Caspary et al 1999;Hu et al 2011;Huang et al 2016). Two studies, Chen et al (2018) in this issue and Hunter et al (2018) in the previous issue of Genes & Development, highlight the significance of IGF2 up-regulation in the context of Perlman syndrome and Wilms tumor, respectively.…”

“…However, interestingly, three of the four Wilms tumors that developed in Perlman patients also had loss of imprinting or loss of heterozygosity of IGF2 (Wegert et al 2015;Gadd et al 2017), implicating an additive effect. It is not surprising that Wilms tumors did not develop in the Dis3l2 mutant mice because it has been shown that, in mouse models, Wilms tumor arises only if Igf2 up-regulation is on the background of additional mutations, such as in Wt1 (Hu et al 2011;Huang et al 2016). The absence of over-growth phenotype in these mutants could be because of species-and tissue-specific promoter usage, which needs to be investigated separately.…”