Defining cellular states of quiescence in human brain tumors

定义人脑肿瘤的细胞静止状态

基本信息

批准号：
10531265
负责人：
Patrick Paddison
金额：
$ 51.54万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-15 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10531265
关键词：
Acetyltransferase Adjuvant Therapy Adopted Biological Assay Biological Models Biology Brain Neoplasms CRISPR screen Cancer Model Caring Cell Cycle Cells Chromatin Clinic Clinical Collection Communities Complex Data Data Set Development Experimental Models Failure G0 Phase Gene Expression Genes Genetic Transcription Genomics Glioblastoma Glioma Grant Growth HTATIP gene Human Indolent Knowledge Lysine Machine Learning Malignant Neoplasms Maps Mediating Methods Mitosis Modeling Molecular Neoplasm Metastasis Oncogenes Outcome Pathway interactions Patients Phenotype Population Primary Neoplasm Public Health RNA Radiation Recurrence Recurrent tumor Regulation Reporter Resistance Resources Ribosomal DNA Role Sampling Secondary to Solid Solid Neoplasm Stress System Testing Treatment Protocols Xenograft procedure chemoradiation conventional therapy epigenetic regulation experimental study functional genomics gene function gene network improved in vivo inhibitor machine learning method member neoplasm resource neoplastic cell neurogenesis novel novel therapeutic intervention prevent response single cell analysis single-cell RNA sequencing standard of care stem-like cell temozolomide therapeutic candidate therapeutic target therapeutically effective therapy resistant tool treatment response tumor tumor heterogeneity

项目摘要

PROJECT SUMMARY The most aggressive type of brain tumor, grade IV glioma known as glioblastoma (GBM), is one of the few tumor types with both a poor outcome and minimal improvement in survival in the past decades. For GBM, like other solid cancers, intratumoral heterogeneity is likely an important factor in mediating therapeutic response. In particular, quiescent, G0-like subpopulations may engender tumors with more robust responses to treatment regimens and allow for tumor regrowth after standard of care (SOC). However, G0-like tumor populations are currently ill-defined, even after application of single cell genomics to GBM. Our failure to fully comprehend and experimentally model quiescent/G0-like states represents a critical knowledge gap, but also a key opportunity, for glioma and other cancers, as neutralizing G0 cells could effectively prevent chemoradiotherapy resistance and tumor recurrence. The purpose of this grant is to provide a functional and molecular definition of G0-like states in GBM tumors and their responses to SOC. In Aim 1, we will define molecular networks governing long- and short-term quiescent states in GBM patient tumors using a novel G0 reporter system in combination with single cell genomic analysis. In Aim 2, we will test the hypothesis that dormant G0 GBM cells have unique RNA and chromatin signatures required for SOC survival and tumor regrowth. In Aim 3, we will study and nominate the NuA4/KAT5 lysine acetyltransferase complex as a key regulator of G0-like states in GBM and candidate therapeutic target. The Aims are built on strong preliminary data, including: the creation of a machine learning-based method for identifying G0-like cells in gliomas, integrated analysis of single cell RNA and chromatin analysis of primary and PDX GBM tumors with standard of care, a functional genomic screen to identify regulators of GBM G0, and key experimental models to functionally dissect G0 states in GBM tumor models. If successful, this grant will produce a new working model for GBM G0-like states, provide key genes and gene networks associated with G0, and analysis tools for identifying G0-like states in clinical samples. It will also define how these populations respond to SOC and shift tumor dynamics during recurrence. Finally, it will provide data for a new therapeutic strategy, "downgrading", where grade IV tumors are made less aggressive by triggering extended or permanent G0-like states in tumor cells.

项目概要最具侵袭性的脑肿瘤类型，IV 级神经胶质瘤，称为胶质母细胞瘤 (GBM)，是少数几种肿瘤之一在过去的几十年里，这些类型的结果不佳，生存率改善甚微。对于 GBM 来说，和其他的一样对于实体癌，瘤内异质性可能是介导治疗反应的重要因素。在特殊的、静止的、G0 样亚群可能会产生对治疗有更强烈反应的肿瘤治疗方案并允许标准护理（SOC）后肿瘤再生。然而，G0 样肿瘤群体即使在将单细胞基因组学应用于 GBM 之后，目前仍不清楚。我们未能充分理解和实验模型静态/类似 G0 的状态代表了一个关键的知识差距，但也是一个关键的机会，对于神经胶质瘤和其他癌症，中和 G0 细胞可以有效防止放化疗耐药和肿瘤复发。这笔资助的目的是提供 GBM 肿瘤中 G0 样状态的功能和分子定义他们对 SOC 的反应。在目标 1 中，我们将定义控制长期和短期静态的分子网络使用新型 G0 报告系统结合单细胞基因组分析对 GBM 患者肿瘤进行状态分析。在目标 2 中，我们将检验休眠 G0 GBM 细胞具有独特 RNA 和染色质特征的假设 SOC 存活和肿瘤再生所需的。在目标 3 中，我们将研究并提名 NuA4/KAT5 赖氨酸乙酰转移酶复合物作为 GBM 中 G0 样状态的关键调节剂和候选治疗靶点。这些目标建立在强大的初步数据之上，包括：创建基于机器学习的方法识别神经胶质瘤中的 G0 样细胞、单细胞 RNA 的综合分析以及原代细胞和细胞的染色质分析 PDX GBM 肿瘤采用标准护理、功能基因组筛选来识别 GBM G0 的调节因子以及关键功能性剖析 GBM 肿瘤模型中 G0 状态的实验模型。如果成功，这笔赠款将为 GBM G0 样状态产生新的工作模型，提供关键基因和基因与 G0 相关的网络，以及用于识别临床样本中类似 G0 状态的分析工具。它还将定义这些人群如何响应 SOC 并在复发过程中改变肿瘤动态。最后，它将提供新治疗策略“降级”的数据，其中 IV 级肿瘤的侵袭性降低触发肿瘤细胞中延长或永久的 G0 样状态。