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(PQ1) Identifying and targeting human glioblastoma migrating in the peritumoral niche

(PQ1) 识别和靶向在瘤周微环境中迁移的人类胶质母细胞瘤

基本信息

批准号：
9883759
负责人：
Melanie Hayden Gephart
金额：
$ 35.97万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883759
关键词：
Adult Affect Astrocytes Biological Assay Brain Candidate Disease Gene Cell Line Cell Migration Pathway Cell Separation Cells Coculture Techniques Code Data Development Diagnostic radiologic examination Disease Drowning Excision Galectin 1 Gene Expression Gene Expression Profile Genes Genetic Markers Genetic Transcription Glioblastoma Grouping Histologic Human Image Immunohistochemistry In Vitro Individual Lead Malignant - descriptor Malignant neoplasm of brain Maps Methods Microscopic Microtomy Migration Assay Modeling Mus Neurosurgeon Operative Surgical Procedures Pathway interactions Patients Peptides Positioning Attribute Pre-Clinical Model Primary Brain Neoplasms Primary Cell Cultures Process Radiation Rodent Sampling Scientist Serum-Free Culture Media Slice Specimen Techniques Testing Therapeutic Time Tissue imaging Validation Xenograft Model Xenograft procedure brain cell cell motility cell type fetal fetus cell gene interaction genetic signature human disease human tissue improved innovation interest knock-down migration multidisciplinary neoplastic cell nerve stem cell new therapeutic target novel personalized medicine premalignant response scaffold single cell analysis single-cell RNA sequencing transcriptome transcriptome sequencing tumor validation studies wound healing

项目摘要

Glioblastoma, the most common and deadly primary brain tumor, disseminates widely throughout the brain by hijacking the cell migration pathways used by normal neural stem cells. Migrating glioblastoma persist in the surrounding brain (pre-malignant field) after tumor resection, ultimately recurring and killing the patient. Glioblastoma migration is the hallmark of this devastating disease, yet no one has isolated and analyzed the single cell transcriptome of migrating glioblastoma as compared to normal (mature and fetal) or peritumoral astrocytes. We propose that migrating glioblastoma and peritumoral astrocytes employ fetal astrocyte genes to promote glioblastoma migration, that these genes are consistent within and across patients, and that inhibition of these genes will halt glioblastoma migration. To deconstruct and target glioblastoma migrating within the human peritumoral astrocyte microniche and suggest personalized therapies for patients, we have developed three innovative methods that leverage primary human tissue. Aim 1: To determine the extent to which migrating glioblastoma are defined by human fetal astrocyte gene expression, distinct from normal and glioblastoma astrocytes. Single cell isolation, RNA-seq, and transcriptome analysis of matched human glioblastoma, peritumoral, and normal brain will be used to identify brain cellular subtypes and migrating glioblastoma within the peritumoral brain. Migrating glioblastoma genetic markers that overlap with fetal astrocyte genes and are consistent within and across samples will be further validated. Aim 2: To test the extent to which peritumoral astrocytes facilitate glioblastoma migration through fetal astrocyte gene expression. Matched human glioblastoma and peritumoral astrocytes, isolated from fresh surgical specimens through our novel immunopanning separation technique, will undergo RNA-seq and culture. We suspect transcriptional and functional similarities between peritumoral astrocytes and normal fetal astrocytes. Candidate pathways will be promoted or inhibited in transwell migration assays using primary human glioblastoma. Aim 3: To test whether glioblastoma migration can be inhibited through knockdown of either fetal astrocyte genes in migrating glioblastoma or peritumoral astrocytes. Candidate genes identified in migrating glioblastoma (Aim 1) and peritumoral astrocytes (Aim 2) hold therapeutic promise, and will first be validated using primary human glioblastoma in vitro and ex vivo. Targets showing promise in these validation studies of either migrating glioblastoma or peritumoral astrocytes will undergo human glioblastoma- in-mouse intracranial xenograft modeling. Control and primary specimens will be imaged with CLARITY to confirm the dynamic glioblastoma-peritumoral astrocyte interactions. This project has direct translational potential as targeting glioblastoma migration will confine glioblastoma to a local disease, improving response to surgical resection and radiation by decreasing malignant progression.

胶质母细胞瘤是最常见和最致命的原发性脑肿瘤，它广泛分布于整个大脑