Defining cellular states of quiescence in human brain tumors

定义人脑肿瘤的细胞静止状态

• 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
• 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

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.

项目摘要 最具侵袭性的脑肿瘤类型，IV级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，这些类型的预后很差，生存率的改善也很小。对于GBM，与其他 在实体癌中，肿瘤内异质性可能是介导治疗反应的重要因素。在 特别是静止期的G 0样亚群可能产生对治疗有更强反应的肿瘤 方案，并允许标准护理（SOC）后肿瘤再生长。然而，G 0样肿瘤群体是 目前尚不明确，即使在单细胞基因组学应用于GBM之后。我们未能充分理解和 实验模型静态/G 0类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，因为中和G 0细胞可以有效地防止放化疗抵抗 和肿瘤复发。 这项资助的目的是提供GBM肿瘤中G 0样状态的功能和分子定义， 在目标1中，我们将定义控制长期和短期静止的分子网络， 使用新的G 0报告系统与单细胞基因组分析相结合，在GBM患者肿瘤中观察到的状态。 在目标2中，我们将检验休眠的G 0 GBM细胞具有独特的RNA和染色质特征的假设 SOC存活和肿瘤再生长所需的。在目标3中，我们将研究并命名NuA 4/KAT 5赖氨酸 乙酰转移酶复合物作为GBM中G 0样状态的关键调节剂和候选治疗靶点。 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， 鉴定胶质瘤中的G 0样细胞，单细胞RNA的综合分析和原发性和 PDX GBM肿瘤与标准护理，功能基因组筛选，以确定GBM G 0的调节因子， 实验模型来功能性地剖析GBM肿瘤模型中的G 0状态。 如果成功的话，这项资助将为GBM G 0样状态产生一个新的工作模型，提供关键基因和基因治疗。 与G 0相关的网络，以及用于识别临床样本中G 0样状态的分析工具。它还将 定义这些人群对SOC的反应，并在复发期间改变肿瘤动力学。最后，它将提供 一种新的治疗策略的数据，“降级”，其中IV级肿瘤的侵袭性较低， 触发肿瘤细胞中延长或永久的G 0样状态。