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

• 批准号: 10303024
• 负责人: Michael Clark Oldham
• 金额: $ 42.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/10303024
• 关键词: Adult; Architecture; Astrocytoma; Biological Markers; Biopsy Specimen; Brain; Brain Neoplasms; Cell Differentiation process; Cell Nucleus; Cells; Cerebral cortex; Collaborations; Complementary DNA; DNA Methylation; Data; Diffuse; Dissociation; Exhibits; Frozen Sections; Gene Expression; Gene Expression Profile; 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; Mutation Analysis; Nature; Neurosciences; Non-Malignant; Oncogenic; Outcome; Phenotype; 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; man; molecular phenotype; multiple omics; mutant; novel; novel strategies; oligodendroglioma; subclonal heterogeneity; transcriptome; transcriptome sequencing; treatment strategy; tumor

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 弥漫性胶质瘤是成人最常见的原发恶性脑肿瘤。现有的治疗方法只能提供 受益不大，因此迫切需要新的治疗策略。对胶质瘤的遗传学研究 发现了一些反复发生的突变，激发了许多重要的努力，以开发有针对性的治疗方法。 然而，由于这些努力何时或是否会成功尚不确定，因此扩大治疗范围至关重要。 神经胶质瘤的TIC搜索空间。像所有癌症一样，导致胶质瘤的突变通过改变细胞身份来改变细胞身份。 ING基因表达。然而，区分恶性胶质瘤细胞和细胞的转录表型 正常成人大脑中细胞对胶质瘤微环境的影响仍然知之甚少。这位亲王- 项目将使用新的分析和实验策略来精确定义转录表型， 最可靠地区分胶质瘤的恶性和非恶性细胞类别与正常成人的细胞。 人类的大脑。我们的中心假设是，完整组织样本的整合基因共表达分析可以 揭示胶质瘤中不同细胞类别的核心转录特性，从而突出 胶质瘤基因分型对基因表达的影响。在目标1中，我们将执行荟萃分析和综合反卷积 来自星形细胞瘤、少突胶质细胞瘤和胶质母细胞瘤的4K完整组织样本的转录本 提取不同细胞类别的转录图谱。我们将比较特定细胞类别的转录信号- 在胶质瘤和正常大脑之间的图像，并验证组织学预测的差异。在目标2中，我们将 确定低级别胶质瘤中IDH1 R132H+恶性细胞最一致的分子表型 通过对冻菜连续切片中突变等位基因频率和分子特征的协变分析，确定了冻菜连续切片的分子特征。 更多的标本。我们将通过组织学和与正常人脑的比较来验证预测。 在目标3中，我们将对空间定位的亚克隆多样性进行多尺度和多组学分析。 低级别胶质瘤的巨细胞。我们将通过TAR-来验证亚克隆多样性和转录表型。 获得单核RNA-seq.总的来说，这些实验将提供对分子的基本见解。 促进胶质瘤形成并显著扩大成人肥胖症治疗研究空间的机制 恶性胶质瘤。