Molecular characterization of Wilms' Tumor: insights from single nucleus analystics on Wilms' Tumor development and oncogenesis

Wilms tumors are known to arise from and maintain features of the embryonic kidney associated with a surprisingly heterogenous genetic and molecular landscape. To further investigate both intra-tumor and inter-tumor variability, single nucleus RNA-sequencing (snRNA-seq) was performed on favorable histology Wilms tumors capturing blastema, epithelial, and stromal components, which were analyzed in comparison to a normal kidney reference atlas established from kidney samples (including patient-matched adjacent kidney) as well as publicly available single-cell RNA-seq from 18-week human fetal kidney. The transcriptomic profiles from Wilms tumor nuclei were shown to recapitulate its known triphasic histology, with similar gene expression signatures corresponding to nephron progenitor cells as well epithelial and stromal cells from human fetal kidneys. Tumors additionally show a high percentage of cycling cells in the G2/S phase, including tumor samples with blastemal cells both resembling “uninduced” nephron progenitors as well as tumor samples with blastema expressing more “differentiated” signatures of early proximal tubules, podocytes, as well as stromal/muscle genes. Furthermore, pathway enrichment analyses in the blastemal components show nephron/kidney epithelial development as expected, but interestingly also show neuronal/axon signatures across the majority of tumor samples. Additionally, enriched pathways in a subset of the tumors include WNT and TGF-beta signaling in the non-cycling blastema and polycomb repressive complex in cycling blastemal cells, suggesting that Wilms tumor blastema not only shows significant heterogeneity in its differentiation state/trajectory but also in its potential biological pathways/drivers.