Understanding the cellular inventory of pediatric kidney tumors

儿童肾肿瘤在遗传、表型和临床病程方面具有高度多样性。约90%为肾母细胞瘤，而透明细胞肉瘤（CCSK）和先天性间母细胞肾瘤（CMN）较少见。这些肿瘤被认为是由于胎儿肾前体的流产或错误发育而产生的，它们表现出惊人的组织学多样性。临床挑战是更好地确定加强治疗的高风险病例，并安全地确定低风险病例，从而进一步降低治疗强度。由于临床分类的局限性，迫切需要对儿童肾癌的各种亚型及其对临床病程的影响有更深入的生物学认识。我们过去已经确定了这些肿瘤的一些致癌驱动因素，但大多数与肿瘤的表现和病程无关。尤其是胚质和间变性的病例给治疗带来挑战，对前体病变和罕见亚型的分类和早期检测具有很高的临床意义。基于德国Wilms肿瘤生物库的优秀资源，我们已经在初步工作中表明，单细胞基因表达分析可以以前所未有的分辨率和深度定义这些肿瘤中的特定细胞亚群，这将有助于改善分层。一个例子是对胚细胞亚群的检测，这些亚群是出于临床原因而假定的，但无法从组织学上定义——这是通过组织rna测序不可能实现的。我们建议将这种方法扩展到更多的病例，特别是胚质和间变性肿瘤、肾源性肿瘤以及相关实体CCSK和CMN。我们将依靠细胞核的单细胞rna测序，使我们能够利用我们的冷冻肿瘤的综合档案，并附上优秀的临床数据。主要目的是在细胞水平上表征这些儿童肾肿瘤的异质性，以更好地了解组织学区室内部和之间的动态细胞相互作用和依赖性，这将为未来的诊断和治疗方法提供信息。实验方法和生物信息学工具都在不断快速发展，我们已经在寻求策略来优化这些肿瘤队列的输出，以最大限度地提高信息的产量。新的分类标记和信号通路的解除将在德国Wilms肿瘤生物库（bbb14400个冷冻样本）的扩展收集中与参考病理学相结合进行验证。申请人是在各自的儿科肾肿瘤生物学和单细胞表达分析领域经验丰富和国际公认的专家。他们的共同努力将提高我们对这些肿瘤的细胞组成和谱系关系的理解，提高诊断和分层，并揭示可以利用的关键漏洞。

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.