Understanding the cellular inventory of pediatric kidney tumors

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Pediatric kidney tumors are highly diverse in terms of genetics, phenotype and clinical course. About 90% are Wilms tumors, while clear cell sarcoma (CCSK) and congenital mesoblastic nephroma (CMN) are less common. These tumors are thought to arise through abortive or misguided development of fetal kidney precursors and they display striking histologic diversity. The clinical challenge is to better identify high-risk cases for intensified treatment and to safely define lower risk, where treatment intensity may be further reduced. Since clinical classification reaches its limits, greater biological insight into the various subtypes of pediatric kidney cancer and their influence on clinical course is urgently needed.We have identified a number of oncogenic drivers for these tumors in the past, but most do not correlate with tumor presentation and course. Especially blastemal and anaplastic cases pose therapeutic challenges and classification and early detection of precursor lesions and rare subtypes are of high clinical relevance. Based on the excellent resource of the German Wilms tumor biobank we have shown in preliminary work that single-cell gene expression analyses can define specific subpopulations of cells in these tumors with unprecedented resolution and depth that will be instrumental to improve stratification. An example is the detection of subgroups of blastemal cells that were postulated for clinical reasons but could not be defined histologically – an achievement that would not have been possible by bulk tissue RNA-seq.We propose to extend this approach to larger numbers of cases, in particular to blastemal and anaplastic tumors, nephrogenic rests and the related entities CCSK and CMN. We will rely on single-cell RNA-seq of cell nuclei that allows us to draw on our comprehensive archive of frozen tumors with excellent clinical data attached. The primary goal is to characterize the heterogeneity of these pediatric kidney tumors at the cellular level to better understand the dynamic cellular interactions and dependencies within and between histological compartments, which will inform future diagnostic and therapeutic approaches. Both experimental methods and bioinformatics tools are under constant and fast development and we are already pursuing strategies to optimize output from such cohorts of tumors to maximize the yield of information. Novel classification markers and deregulation of signaling pathways will be validated in extended collections from the German Wilms tumor biobank (>1.400 frozen samples) in conjunction with reference pathology.The applicants are experienced and internationally recognized experts in their respective fields of pediatric kidney tumor biology and single-cell expression analysis. Their joint effort will improve our understanding of cell composition and lineage relationships in these tumors, to improve diagnostics and stratification and to expose critical vulnerabilities that can be exploited.