Understanding the cellular inventory of pediatric kidney tumors

了解小儿肾肿瘤的细胞库存

• 批准号: 419964688
• 负责人: Professor Dr. Manfred Gessler
• 金额: --
• 依托单位: Lehrstuhl für Entwicklungsbiochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/419964688?language=en
• 关键词: Understanding; cellular; inventory; pediatric; kidney

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.

儿童肾脏肿瘤在遗传学、表型和临床病程方面高度多样化。大约90%是肾母细胞瘤，而透明细胞肉瘤（CCSK）和先天性中胚层肾瘤（CMN）不太常见。这些肿瘤被认为是通过胎肾前体细胞的流产或误导性发育而产生的，它们显示出惊人的组织学多样性。临床挑战是更好地识别高风险病例进行强化治疗，并安全地定义低风险，治疗强度可能会进一步降低。由于临床分类已达到极限，因此迫切需要对儿童肾癌的各种亚型及其对临床病程的影响进行更深入的生物学研究。我们过去已经确定了这些肿瘤的许多致癌驱动因素，但大多数与肿瘤表现和病程无关。特别是胚细胞和间变性病例对治疗提出了挑战，并且前驱病变和罕见亚型的分类和早期检测具有高度的临床相关性。基于德国Wilms肿瘤生物库的优秀资源，我们在初步工作中表明，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。一个例子是检测亚组的胚基细胞，假设为临床原因，但不能被组织学上定义-一个成就，这将是不可能的散装组织RNA-seq。我们建议将这种方法扩展到更多的情况下，特别是胚基和间变性肿瘤，肾源性剩余和相关实体CCSK和CMN。我们将依赖于细胞核的单细胞RNA-seq，这使我们能够利用我们的冷冻肿瘤综合档案，并附上优秀的临床数据。主要目标是在细胞水平上表征这些儿科肾脏肿瘤的异质性，以更好地了解组织学分区内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群的输出，以最大限度地提高信息产量。新的分类标志物和信号通路的失调将在来自德国Wilms肿瘤生物库的扩展集合（>1.400个冷冻样本）中结合参考病理学进行验证。申请人是儿科肾脏肿瘤生物学和单细胞表达分析各自领域的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中细胞组成和谱系关系的理解，改善诊断和分层，并暴露可被利用的关键漏洞。