Defining the Role of Beta-Catenin Activation in Wilms Tumor
Abstract
Wilms tumor resembles the developing kidney, consisting of blastema/nephron progenitor cells NPCs, epithelium, and stoma-indicating a link between the dysregulation of normal development and tumorigenesis. Loss of Wt1 (Wilms tumor 1) and activation of beta-catenin has been shown in a significant proportion of Wilms tumors, however, their role(s) in tumorigenesis remain poorly understood. While it has long been assumed that NPCs act as a cancer stem cell, mouse models with activation of beta-catenin within the NPC lineage paradoxically show premature loss of blastema, a phenotype opposite to Wilms tumor. Given that we and other have shown that disrupting signals from developing renal stroma results in abnormally maintained NPCs (reminiscent of nephrogenic rests), we hypothesized that signaling from the stroma, specifically activation of beta-catenin, contributes to Wilms tumor development. Through this work, we have shown that activation of beta-catenin in stromal progenitors inhibits NPC differentiation, and comparisons of the transcriptomes from human tumors to mutant mouse kidneys with beta-catenin activation in the stromal vs, NPC lineages revealed that human Wilms tumor more closely resembled stromal mutants. Furthermore, we examined mutant mouse models with concurrent beta-catenin and Wt1 mutations in an effort to understand how defects in progenitor cell maintenance and differentiation, potentially related to abnormal progenitor cell crosstalk during development, may play a unifying role in the predisposition to Wilms tumor.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2021
- Accession Number
- AD1169101
Entities
People
- Keri Drake
Organizations
- University of Texas at Austin