Center for pediatric tumor cell atlas

项目概要-总体 儿童癌症是儿童死亡的第二大常见原因。儿童癌症发病率很高 与成年人不同。原因、机制和治疗方法不能从 对成人恶性肿瘤的研究。为了影响儿童癌症的负担，需要对以下方面进行具体研究： 儿科癌症因此，我们提出了三个具体的儿科亚型的深入表征， 恶性肿瘤占所有儿童癌症死亡的50%以上：高级别胶质瘤（pHGG）， 高危神经母细胞瘤（NB）和极高危急性淋巴母细胞性B细胞前体白血病（VHR-ALL）。所有 三种肿瘤类型具有对治疗的典型初始反应的特征，随后出现 抵抗力和难治性疾病。我们将绘制肿瘤细胞的分子和细胞变化， 微环境和免疫系统使用全面的多维单细胞和原位 与两个关键转变相关的技术：初始反应和抗药性疾病的出现- 两者都是高优先级的过渡。治疗方式将包括标准化疗、分子靶向化疗、放射治疗和放射治疗。 治疗和嵌合抗原受体（CAR-）T细胞治疗，抓住了当前癌症的最前沿 疗法最终产品将以以下方式影响全球儿童癌症研究：1）肿瘤 地图集：地图集将提供一个高度用户友好的、公开可用的、可搜索的数据库， 对三种最致命的儿童癌症进行全面的多组学单细胞分析。分子数据将 通过访问额外的病理学评估、临床和结局数据进行丰富的注释，并授予 访问源数据，例如肿瘤成像。2)计算方法：除了数据之外， 该项目中使用的计算工具和管道将提供给研究界。这些 包括用于处理多组学和原位数据的方法和管道，癌症发生学的推断， 细胞和克隆特异性途径推断、用于推断细胞间串扰的方法以及数据库 用于查询、探索和可视化高度复杂数据的算法。3)获取生物样本， 后续研究：本项目中收集的生物标本将被储存起来，并提供给生物医学研究所。 研究社区。这些包括组织切片、有活力的冷冻标本和患者来源的异种移植物 (PDX模型）。总之，拟议项目将寻求解决儿科的主要公共卫生需求， 广泛影响整个研究界，并根据一个复杂的 了解驱动儿科癌症的关键分子回路。

PROJECT SUMMARY - OVERALL Childhood Cancer is the second most common causes of childhood deaths. Cancers in children are highly distinct from those in adults. Causes, mechanisms and therapeutic approaches cannot be extrapolated from the study of adult malignancies. To impact the burden of pediatric cancers requires the specific study of pediatric cancers. We therefore propose the in depth characterization of three specific subtypes of pediatric malignancies which, together, account for over 50% of all pediatric cancer deaths: high grade glioma (pHGG), high risk neuroblastoma (NB), and very high risk acute lymphoblastic B-cell precursor leukemia (VHR-ALL). All three tumor types share a characteristic of typically initial response to therapy, followed by the emergence of resistance and refractory disease. We will map molecular and cellular changes in tumor cells, microenvironment and the immune system using comprehensive multi-dimensional single-cell and in situ technologies associated with two critical transitions: initial response, and emergence of resistant disease – both high-priority transitions. Treatment modalities will include standard chemotherapy, molecular targeted therapies and chimeric antigen receptor (CAR-) T cell therapy, capturing the cutting edge of current cancer therapy. The final product will impact global childhood cancer research in the following manner: 1) Tumor Atlases: atlases will provide a highly user friendly, publicly available, searchable database of the most comprehensive multi-omic, single cell analysis of the three most lethal childhood cancers. Molecular data will be richly annotated with access to additional pathological evaluation, clinical and outcomes data, and grant access to source data such tumor imaging. 2) Computational methods: in addition to the data, the critical computational tools and pipelines used in this project will be available to the research community. These include methods and pipelines for processing multi-omics and in situ data, inference of cancer phylogeny, inference of cell- and clone-specific pathways, methods for inferring cell-cell crosstalk, as well as database algorithms for the query, exploration and visualization of highly complex data. 3) Access to biospecimens for follow up studies: biospecimens collected in this project will be banked and made available to the biomedical research community. These include tissue sections, viably frozen specimen, and patient derived xenograft (PDX models). In summary, the proposed project will seek to address a major public health need in pediatrics, broadly impact the entire research community, and jumpstart target discovery based on a sophisticated understanding of the key molecular circuits that drive pediatric cancer.