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：
10018940
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/10018940
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 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 stem cells 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.

摘要摘要脑肿瘤因其多样性、患病率和贫困而造成巨大的疾病负担对治疗的反应以及美国超过 50 万人的高发病率和死亡率。患有原发性脑肿瘤或其他中枢神经系统肿瘤，并且大约有 80,000 个新肿瘤然而，每年都会诊断出脑肿瘤的起源——即每个大脑的特定细胞类型。肿瘤的出现仍然是个谜，并且是我们对其生物学理解的一个根本未知数。该项目将通过开发一种新型单细胞基因组学技术来识别细胞，从而解决这一重大差距动物模型表明，“起源细胞”——第一个细胞——的表型。获得引发肿瘤的基因突变——通常在决定后续肿瘤中发挥重要作用起源细胞的表观遗传遗产可能在人类脑肿瘤中发挥作用。好吧，但是由于重大技术问题，肿瘤细胞起源的鉴定还不可能局限性——缺乏系统追踪人体组织细胞谱系的方法。通过三个相关目标来应对这一研究挑战：1）开发一种称为 TAPESTRY 首次能够从人体组织重建高分辨率谱系树。 TAPESTRY 将通过选择性捕获数十种自发发生的体细胞突变来实现这一目标。数千个单细胞，同时分析相同单细胞的转录组，从而允许以可行的成本重建表型注释的谱系树 2) 应用； TAPESTRY 对正常大脑皮层中祖细胞谱系的层次结构进行编目作为参考，然后识别该层次结构中单个脑肿瘤的起源细胞和早期谱系。该目标将重点关注三种可能具有不同来源细胞的肿瘤类型：胶质母细胞瘤（最常见和最常见的肿瘤） 3）在对 TAPESTRY 识别的早期肿瘤谱系进行原位空间绘图，以了解它们是否占据肿瘤内的特定结构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。将深入了解脑肿瘤病因学中一个重要的未知因素——起源细胞——我们以前在肿瘤生物学中发挥着重要但未被充分认识的作用。改变我们对脑肿瘤为何在何时何地出现、其表型多样性以及重要的是，可以促进早期检测、新动物模型的创建以及谱系的设计此外，这里开发的技术有可能对癌症产生重大影响。更广泛的生物学和发育生物学研究。