Primary brain tumors are remarkably diverse, with more than 100 different defined types. This large diversity of brain tumors approximates the diversity of cell types in the normal brain, suggesting that each type of brain tumor corresponds to a different cell of origin transformed by a particular set of driver mutations to which it is susceptible. Definitive evidence that an individual brain tumor or type of tumor arises from a particular cell type requires a method for tracing cell lineages directly in humans.
Our prior work has developed methods for sequencing the entire genomes of single cells from the brain. This has revealed remarkable levels of somatic mutations that could in principle be used as lineage markers to trace the origins of brain tumors directly in human tissues.
What are the goals of this project?
The goals of this project are to apply novel single-cell genome sequencing technologies for lineage tracing of pediatric brain tumors, with the goal of identifying their lineage(s) of origin. and to analyze CBTN-generated genomic data from pediatric tumors to profile somatic mutational processes that preferentially occur in lineage-expressed genes
What is the impact of this project?
We will directly address a major gap in our ability to determine the origins of pediatric brain tumors by developing and applying novel single-cell technologies for high-resolution lineage tracing of human brain tumors. High-resolution lineage tracing of pediatric brain tumors for the first time may enable a paradigm shift in our ability to answer previously inaccessible questions about brain tumor origins and lineages. They could also help reveal the clonal evolution of tumors and how in vivo selective forces (e.g. hypoxia, nutrient supply, chemotherapy, immunologic) sculpt their evolution and cellular heterogeneity. Similarly, they could be used to determine the lineages from which metastases arise. Finally, it could rigorously test hypotheses about tumor-propagating cancer stem cells (a distinct concept from the tumor-initiating cell of origin) and possible hierarchical organization of tumor cells, since these would produce characteristic lineage tree patterns.
Why the CBTN request is important to this project?
The CBTN has unique access to and a network for obtaining post-mortem samples that are vital for this work. This is because we are most interested in normal brain tissue adjacent to brain tumors, which is usually not preserved or stored.
Additionally, the CBTN has already sequenced many pediatric brain tumors, which could be immediately used as raw data for our analyses. Comprehensive genomic sequencing of these tumor types is not available anywhere else.
The Children's Brain Tumor Network contributed to this project by providing access to the Pediatric Brain Tumor Atlas and by providing samples from post-mortem collections. (Gift from a Child)
Gilad Evrony, MD, PhD
Gilad is an Assistant Professor at NYU School of Medicine’s Center for Human Genetics and Genomics, and the Departments of Pediatrics and Neuroscience & Physiology. He received his undergraduate degree in Brain and Cognitive Sciences from MIT, and served in the Israel Defense Forces before co
Hassenfeld Children's Hospital at NYU Langone
Medulloblastomas comprise the vast majority of pediatric embryonal tumors and by definition arise in the posterior fossa, where they constitute approximately 40% of all posterior fossa tumors. Other forms of embryonal tumors each make up 2% or less of all childhood brain tumors.The clinica
High-grade glioma/astrocytoma (WHO grade III/IV)
High-grade Gliomas (HGG) in children nearly always result in a dismal prognosis. Although novel therapeutic approaches are currently in development, preclinical testing has been limited, due to a lack of pediatric specific HGG preclinical models. These models are needed to help test the effective
Low-Grade astrocytomas are the most common cancer of the central nervous system in children. They represent a heterogeneous group of tumors that can be discovered anywhere within the brain or spinal cord. Although surgical resection may be curative, up to 20% of children still suffer from the eff