Stromal beta-catenin activation impacts nephron progenitor differentiation in the developing kidney and may contribute to Wilms tumor.

Wilms tumor (WT) morphologically resembles the embryonic kidney, consisting of blastema, epithelial, and stromal components, suggesting tumors arise from the dysregulation of normal development. Beta-catenin activation is observed in a significant proportion of WTs; however, much remains to be understood about how it contributes to tumorigenesis. While activating beta-catenin mutations are observed in both blastema and stromal components of WT, current models assume that activation in the blastemal lineage is causal. Paradoxically, studies performed in mice suggest that activation of beta-catenin in the nephrogenic lineage results in loss of nephron progenitor cell (NPC) renewal, a phenotype opposite to WT. Here, we show that activation of beta-catenin in the stromal lineage non-autonomously prevents the differentiation of NPCs. Comparisons of the transcriptomes of kidneys expressing an activated allele of beta-catenin in the stromal or nephron progenitor cells reveals that human WT more closely resembles the stromal-lineage mutants. These findings suggest that stromal beta-catenin activation results in histological and molecular features of human WT, providing insights into how alterations in the stromal microenvironment may play an active role in tumorigenesis.