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

ABSTRACT: Wilms tumor (WT) morphologically resembles the embryonic kidney, consisting of blastema, epithelial, and stromal components, suggesting tumors arise from the dysregulation of normal development. Activation of beta-catenin is observed in a significant proportion of human 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 human WT, current models assume that activation in the blastemal lineage is causal. Paradoxically, studies performed in mice suggest that activation of b-catenin in this 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 acts non-autonomously, resulting in expansion of NPCs and an inhibition of differentiation. 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 stroma signaling may play an active role in tumorigenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE150074 | GEO | 2020/05/08

REPOSITORIES: GEO