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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.

总结抽象