Defining the Role of Beta-Catenin Activation in Wilms Tumor
Abstract
Wilms tumor is the most common type of kidney cancer in children and is thought to arise from abnormal cells within the developing kidney. Early in pregnancy, around the 5th week of gestation, the kidney begins to form from three types of cells, specifically, nephron progenitor cells, epithelial/tubule cells, and stromal progenitor cells, which subsequently give rise to nearly all the cells that make up a mature kidney. However, Wilms tumors are thought to form when developing kidney cells and/or tissue undergo a malignant transformation, resulting in a tumor consisting of cell populations similar to those seen in development, with blastema/nephron progenitor cells and immature epithelial and stromal components. In a normal human kidney, nephron progenitor cells are exhausted prior to birth. However, in Wilms tumor, blastemal/nephron progenitor cells are abnormally persistent. It has long been assumed that the causal mutation in Wilms tumors occurs in the blastemal/nephron progenitor cell component, causing these cells to act as a cancer stem cell and give rise to the different components of Wilms tumor. However, recent studies in mice and humans have suggested that mutations in Wilms tumor genes in the nephron progenitor component alone are not sufficient to cause Wilms tumor, raising the questions, what cell type(s) drive Wilms tumor formation, and what is the underlying mechanism how developing cells become malignant and result in cancer? One key signaling pathway identified in Wilms tumor is the WNT/beta-catenin pathway. WNT/beta-catenin has been previously studied in kidney development and has been shown to regulate many different processes in several different cell types during normal development. However, little is known about its role in Wilms tumor. Using mouse models, we and others have examined beta-catenin signaling in nephron progenitor lineage, and paradoxically, it leads to premature loss of the blastema, a phenotype opposite to what is observed in Wilms tumor. Findings from the Carroll lab and others have recently shown that the renal stroma is an important regulator of nephron progenitor maintenance and differentiation, and loss of this regulation results in blastemal cells/nephrogenic rests, similar to what is seen in Wilms tumor. This led us to hypothesize that activation of beta-catenin in the stroma plays a role Wilms tumorigenesis. To address this, we developed a mutant mouse model with a beta-catenin mutation specific to the developing stroma, and indeed, these kidneys showed epithelial structures surrounded by undifferentiated nephron progenitor cells and spindle-shaped stromal cells, similar to human Wilms tumor. Using genetic mouse models and further characterization of human Wilms tumor samples as outlined in our proposal, our main scientific objective is to better understand the role of beta-catenin in Wilms tumor by specifically examining how stromal beta-catenin mutations regulate stroma-to-nephron progenitor crosstalk and examining the direct oncogenic potential of the stroma in tumor formation. The overall goal of this basic science proposal is to better understand Wilms tumor biology, since all Wilms tumors are thought to arise from problems during development, yet no unifying mechanism of pathogenesis has been identified. While Wilms tumor accounts for only a small percentage of all types of kidney cancer, it is a devastating disease for children. Though the overall survival rate is approximately 90%, improvement in relapse-free survival has plateaued, and current treatment regimens consisting of chemotherapy, radiation, and surgery result in significant morbidity for survivors later in life. Additionally, patients with unfavorable histology and advanced disease have dramatically worse outcomes, with survival rates around 50%, highlighting the need to develop targeted therapies for Wilms tumor. The ultimate applicability of this research is to better understand the eti
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910751
Entities
People
- Keri Drake
Organizations
- United States Army
- University of Texas Southwestern Medical Center