Decoding the molecular basis of cellular identity in adult malignant gliomas

解码成人恶性神经胶质瘤细胞身份的分子基础

基本信息

批准号：
10533784
负责人：
Michael Clark Oldham
金额：
$ 42.18万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10533784
关键词：
Adult Architecture Astrocytoma Biological Markers Biopsy Specimen Brain Brain Neoplasms Cell Differentiation process Cell Separation Cells Cerebral cortex Collaborations Complementary DNA DNA Methylation Data Diffuse Dissociation Exhibits Frozen Sections Gene Expression Gene Expression Profile Gene Expression Profiling Gene Frequency Genes Genetic Transcription Genetic study Genotype Glioblastoma Glioma Gliomagenesis Goals Histologic Histology Human Individual Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Maps Meta-Analysis Methods Molecular Mutation Nature Neurosciences Non-Malignant Oncogenic Outcome Phenotype Qualifying RNA Recurrence Reproducibility Research Sampling Sampling Biases Site Specimen Testing Therapeutic Tissue Sample Tissues Transcript Variant cancer cell design experimental study in silico insight malignant phenotype metaplastic cell transformation molecular phenotype multiple omics mutant novel novel strategies novel therapeutic intervention oligodendroglioma single nucleus RNA-sequencing subclonal heterogeneity transcriptome treatment strategy tumor

项目摘要

Project Summary Diffuse gliomas are the most common primary malignant brain tumors in adults. Existing therapies provide only modest benefits, so there is a pressing need for new treatment strategies. Genetic studies of gliomas have identified a number of recurrent mutations, inspiring many important efforts to develop targeted treatments. Nevertheless, because it is uncertain when or if these efforts will succeed, it is critical to expand the therapeu- tic search space for gliomas. Like all cancers, mutations that cause gliomas transform cellular identity by alter- ing gene expression. However, the transcriptional phenotypes that distinguish malignant glioma cells and cells of the glioma microenvironment from cells in the normal adult human brain remain poorly understood. This pro- ject will use novel analytical and experimental strategies to precisely define the transcriptional phenotypes that most reliably distinguish malignant and non-malignant cell classes in glioma from cells in the normal adult hu- man brain. Our central hypothesis is that integrative gene coexpression analysis of intact tissue samples can reveal the core transcriptional identities of distinct cell classes in gliomas, thereby highlighting the impact of glioma genotypes on gene expression. In Aim 1, we will perform meta-analysis and integrative deconvolution of transcriptomes from >4K intact tissue samples from astrocytomas, oligodendrogliomas, and glioblastomas to distill transcriptional profiles of distinct cell classes. We will compare cell class-specific transcriptional signa- tures between gliomas and normal brains and validate predicted differences histologically. In Aim 2, we will determine the most consistent molecular phenotypes of IDH1 R132H+ malignant cells in lower-grade gliomas by analyzing covariation of mutant allele frequencies and molecular features over serial sections of frozen tu- mor specimens. We will validate predictions histologically and through comparisons with normal human brain. In Aim 3, we will perform multiscale and multiomic analysis of subclonal diversity in spatially mapped subre- gions of lower-grade gliomas. We will validate subclonal diversity and transcriptional phenotypes through tar- geted single-nucleus RNA-seq. Collectively, these experiments will provide fundamental insights into molecular mechanisms that promote gliomagenesis and substantially expand the therapeutic search space for adult ma- lignant gliomas.

项目摘要弥漫性神经胶质瘤是成年人中最常见的原发性恶性脑肿瘤。现有疗法仅提供适度的好处，因此迫切需要新的治疗策略。神经胶质瘤的遗传研究确定了许多复发突变，激发了许多重要的努力来开发目标治疗。但是，由于不确定这些努力何时或是否成功，因此扩展治疗至关重要神经胶质瘤的搜索空间。像所有癌症一样，引起神经胶质瘤的突变通过替代转化细胞身份 ING基因表达。然而，分歧恶性神经胶质瘤细胞和细胞的转录表型正常成年人脑中细胞的神经瘤微环境的理解仍然很少。这个亲 JECT将使用新颖的分析和实验策略来精确定义转录表型最可靠地区分神经胶质瘤的恶性和非恶性细胞类别与正常成年人的细胞男人的大脑。我们的中心假设是完整组织样品的综合基因共表达分析可以揭示了神经胶质瘤中不同细胞类别的核心转录身份，从而突出了基因表达的神经瘤基因型。在AIM 1中，我们将执行荟萃分析和综合反卷积来自> 4K完整的组织样品的转录组来自星形胶质细胞，寡胶质细胞瘤和胶质母细胞瘤的转录组蒸馏的不同细胞类别的转录曲线。我们将比较细胞类特异性的转录信号 - 神经胶质瘤与正常大脑之间的调查并验证组织学上的预测差异。在AIM 2中，我们将确定下级神经胶质瘤中IDH1 R132H+恶性细胞的最一致的分子表型通过分析突变等位基因频率和分子特征在冷冻Tu-的串行切片上的协方差 MOR标本。我们将通过组织学和与正常人脑的比较来验证预测。在AIM 3中，我们将对空间映射的亚重复中的亚克隆多样性进行多阶层和多构分析下级神经胶质瘤的元素。我们将通过焦油验证亚克隆多样性和转录表型获得了单核RNA-seq。总的来说，这些实验将为分子提供基本见解促进神经胶质作用并大大扩展了成人MA-的治疗搜索空间的机制症状的神经胶质瘤。