Abstract 5047: Impact of kidney progenitor cell differentiation status in Wilms tumorigenesis.

Abstract Wilms Tumor (WT) is a pediatric cancer of the kidney and one of the most common solid tumors of childhood. It is thought to arise from the undifferentiated renal mesenchyme, however, it is unknown which mesenchymal cell type can give rise to WT. The recent identification of different subsets of human WTs with defined gene expression signature, histology and clinical outcomes suggests that the cell differentiation status may be an important factor in the etiology of these subsets. Therefore, we hypothesize that WT can arise from fetal kidney cells at different differentiation stages and that different progenitor populations will result in different types of tumors in biology, pathology and molecular signature. Our lab has generated the first genetic WT mouse model via somatic and mosaic ablation of Wilms Tumor 1 (Wt1), using a Wt1 conditional knockout allele with a ubiquitous tamoxifen-inducible CGH-Cre, and Igf2 biallelic expression. In this model, all types of embryonic kidney cells were randomly targeted. With this successful approach, we now have the ability to test the effect of introducing these alterations (Wt1 ablation in the context of Igf2 up-regulation or activation of β-Catenin) into kidney nephrogenic (Cited1-CreERT2) or stromagenic (Foxd1-CreERT2) progenitor cells. Very interestingly, when the mutations were introduced into the nephrogenic progenitors (Cited1-CreERT), WTs develop. These tumors express human WT markers and show a tubular histology with predominant epithelial cells, which histologically corresponds to the epithelial subset of human WTs. To further characterize the biology of these tumors, we will perform gene expression analysis and proteomic microarray analysis to identify aberrantly dysregulated signaling pathways. This study will provide insight into the cellular etiology of WT which may help to identify new therapeutic approaches. Citation Format: Le Huang, Sharada Mokkapati, Qianghua Hu, Vicki Huff. Impact of kidney progenitor cell differentiation status in Wilms tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5047. doi:10.1158/1538-7445.AM2013-5047