Single-cell genomic approaches to study the cellular origins of brain tumors

研究脑肿瘤细胞起源的单细胞基因组方法

基本信息

批准号：
9794972
负责人：
Gilad David Evrony
金额：
$ 42.38万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9794972
关键词：
Address Animal Model Award Behavior Biology Brain Brain Neoplasms Cancer Biology Catalogs Cell Lineage Cells Central Nervous System Neoplasms Cerebral cortex Child Childhood Classification Clinical DNA Sequence Alteration Department chair Development Development Plans Developmental Biology Diagnosis Disease Doctor of Philosophy Early Diagnosis Enrollment Environment Epigenetic Process Etiology Faculty Financial Support Foundations Freedom Funding Future Genes Genetic Genome Genomic approach Genomics Glioblastoma Grant Histologic Human Human Development Human Genetics In Situ In Vitro Individual Institution Intelligence Israel Laboratories Lead Leadership Libraries Malignant - descriptor Malignant neoplasm of brain Maps Mentors Mentorship Methods Microsatellite Repeats Morbidity - disease rate Mutate Mutation Neurosciences New York Oncogenic Pathogenicity Pathway interactions Pediatrics Phenotype Physicians Play Prevalence Primary Brain Neoplasms Primitive Neuroectodermal Tumor Publications Research Residencies Resolution Resource Sharing Resources Role Scientist Somatic Mutation Stem cells System Technology Testing Time Training Training Support Trees Tumor Biology United States Universities Untranslated RNA Wages Work anaplastic oligodendroglioma anticancer research burden of illness career career development cell type cost experience faculty mentor genetic disorder diagnosis genome sequencing high risk human genomics human tissue innovation insight medical schools meetings migration model design mortality neoplastic cell novel outcome forecast professor programs reconstruction research and development response senior faculty single cell sequencing single cell technology single molecule skills statistics student mentoring targeted treatment transcriptome transcriptomics tumor

项目摘要

Summary Abstract Brain tumors are responsible for an immense burden of disease due to their diversity, prevalence, poor response to therapies, and high morbidity and mortality. More than half a million people in the United States have a primary brain tumor or other central nervous system tumor, and about 80,000 new tumors are diagnosed each year. However, the origins of brain tumors— i.e. the specific cell type from which each brain tumor arises— remains enigmatic and is a fundamental unknown in our understanding of their biology. This project will address this major gap by developing a novel single-cell genomics technology to identify the cells of origin of brain tumors. Animal models have shown that the phenotype of the “cell of origin”— the first cell that acquires the genetic mutations to initiate a tumor— often plays a major role in determining subsequent tumor phenotype and behavior. The epigenetic legacy of the cell of origin is likely at play in human brain tumors as well, but the identification of tumor cells of origin has not been possible due to a major technological limitation— the absence of a method for systematically tracing lineages of cells in human tissues. We will address this research challenge via three related aims: 1) Development of a novel single-cell technology called TAPESTRY capable of reconstructing high-resolution lineage trees from human tissues for the first time. TAPESTRY will achieve this by selectively capturing spontaneously occurring somatic mutations in tens of thousands of single cells, while simultaneously profiling the transcriptomes of the same single cells, thereby allowing reconstruction of phenotypically annotated lineage trees at feasible costs; 2) Application of TAPESTRY to catalogue the hierarchy of progenitor cell lineages in normal cerebral cortex as a reference, followed by identification of the cells of origin and early lineages of individual brain tumors within that hierarchy. This aim will focus on three tumor types with likely different cells of origin: glioblastoma (the most common and most lethal malignant brain tumor), anaplastic oligodendroglioma, and primitive neuroectodermal tumors; 3) In situ spatial mapping of the early tumor lineages identified by TAPESTRY to understand whether they occupy specific domains within tumors and whether they contribute to tumor migration and invasion. Overall, this work will provide insight into a significant unknown factor in brain tumor etiology—the cell of origin—which, we hypothesize plays a major and under-appreciated role in tumor biology. Identifying the cell of origin would transform our understanding of why brain tumors arise where and when they do, their phenotypic diversity, and importantly, could facilitate earlier detection, the creation of new animal models, and the design of lineage- targeted therapies. Moreover, the technology developed here has the potential for major impact across cancer biology and developmental biology research more generally.

摘要摘要脑肿瘤由于多样性，患病率而造成了巨大的疾病燃烧。对疗法的反应以及高发病率和死亡率。美国有超过一百万人患有原发性脑肿瘤或其他中枢神经系统肿瘤，约80,000个新肿瘤是每年被诊断出。但是，脑肿瘤的起源 - 即每个大脑的特定细胞类型出现肿瘤 - 仍然是神秘的，是我们对生物学的理解中的基本未知。这项目将通过开发一种新型的单细胞基因组技术来识别这一主要差距脑肿瘤的起源。动物模型表明，“原籍单元”的表型 - 第一个细胞获取遗传突变以启动肿瘤 - 通常在确定随后的肿瘤中起着重要作用表型和行为。起源细胞的表观遗传遗产可能在人脑肿瘤中起作用好吧，但是由于主要的技术限制 - 缺乏系统地追踪人体组织中细胞谱系的方法。我们将通过三个相关目的应对这一研究挑战：1）开发一种新型的单细胞技术称为能够首次从人体组织重建高分辨率谱系树的挂毯。挂毯将通过选择性地捕获自发发生的体细胞突变来实现这一目标成千上万的单细胞同时分析同一单元的转录组，从而允许以可行的成本重建表面上注释的谱系树； 2）应用挂毯以对正常脑皮质中的祖细胞谱系的层次结构编目作为参考然后鉴定该层次结构内的个体肿瘤的原产细胞和早期谱系。该目标将集中在三种可能不同原始细胞的肿瘤类型上：胶质母细胞瘤（最常见和大多数致命性恶性脑肿瘤），肿瘤性寡胶质瘤和原始神经皮皮肿瘤； 3）in 挂毯确定的早期肿瘤谱系的现场空间映射，以了解它们是否占据肿瘤中的特定域以及它们是否有助于肿瘤迁移和侵袭。总体而言，这项工作将洞悉脑肿瘤病因（原始细胞）中一个重要的未知因素，我们假设在肿瘤生物学中起主要且被低估的作用。识别原点会改变我们对脑肿瘤为何在何时何地出现，表型多样性以及重要的是，可以促进早期发现，新动物模型的创建以及谱系的设计靶向疗法。此外，这里开发的技术有可能在癌症上产生重大影响生物学和发育生物学研究更广泛。