Abstract: PO1858
Characterization of Wilms Tumor and Human Fetal Kidney Using Spatial Transcriptomics
Session Information
- Cancer and Kidney Diseases: Nephrotoxins, RCC, and More
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Onco-Nephrology
- 1500 Onco-Nephrology
Authors
- Perin, Laura, Children's Hospital of Los Angeles, Los Angeles, California, United States
- Petrosyan, Astgik, Children's Hospital of Los Angeles, Los Angeles, California, United States
- Villani, Valentina, Children's Hospital of Los Angeles, Los Angeles, California, United States
- Aguiari, Paola, Children's Hospital of Los Angeles, Los Angeles, California, United States
- Thornton, Matthew Edward, University of Southern California, Los Angeles, California, United States
- Zhou, Shengmei, Children's Hospital of Los Angeles, Los Angeles, California, United States
- Grubbs, Brendan, University of Southern California, Los Angeles, California, United States
- De Filippo, Roger E., Children's Hospital of Los Angeles, Los Angeles, California, United States
- Csete, Marie, University of Southern California, Los Angeles, California, United States
- Lemley, Kevin V., Children's Hospital of Los Angeles, Los Angeles, California, United States
- Sedrakyan, Sargis, Children's Hospital of Los Angeles, Los Angeles, California, United States
- Da Sacco, Stefano, Children's Hospital of Los Angeles, Los Angeles, California, United States
Background
Growing evidence links Wilms tumor (WT) to aberrant nephrogenesis. Studies highlighted the genetic complexity of WT, but little is known about the molecular mechanisms that regulate WT development. Using Spatial transcriptomics (ST), which allows analysis of the gene expression based on morphological context, we showed important differences between WT subtypes and defined the interactive gene networks involved in WT development using human fetal kidney (hFK) as reference.
Methods
Using Visium 10x Genomics, we generated spatial maps of gene expression in human fetal kidney (hFK) andfavorable (stage III) and unfavorable (stage I) WTs. Data were analyzed using Space Ranger software v1.0.0, Seurat v3.2, Panther V14, and Loupe Cell Browser and further analyzed against our previously generated bulk/sc-RNA seq data on the same samples.
Results
ST identified specific clusters in hFK that closely recapitulated the developmental stages of normal nephrogenesis (nephrogenic zone, glomeruli, tubules, and stroma). Unfavorable WT and favorable WT clusters showed heterogeneity of the tumor landscape (blastema, epithelium, and stroma and non-renal phenotypes). Blastema in WT favorable vs. WT unfavorable, though histologically identical, presented different transcriptomics profiles. WTs also showed gene expression typical of muscle tissue (or other non-renal phenotypes) rather than mature kidney structures, which correlated with the histologic absence of mature tubules and glomeruli. Comparative RNA-seq analysis identified cells expressing SIX2 and CITED1 as the root cells of the origin of the WT. Unfavorable WT expressed a higher level of CITED1 in blastema foci and higher expression of uncommitted genes and modulation of inductive nephrogenic signals like WNT and FGF. We also identified genes expressed specifically in WT subtypes and performed a preliminary characterization of the immune milieu of WT.
Conclusion
The spatiotemporal mapping combined with different transcriptomic data highlighted the heterogeneity of the WT subtypes confirming uncommitted nephron progenitors as driving the development of WT. We identified genes that may allow for better stratification of WT and potential therapeutic targets for distinct WT subtypes.
Funding
- Private Foundation Support