Defining cellular states of quiescence in human brain tumors

项目总结 最具侵袭性的脑瘤是被称为胶质母细胞瘤(GBM)的IV级胶质瘤，是为数不多的肿瘤之一 在过去几十年中，预后较差且存活率改善甚微的类型。对于GBM，就像其他 实体癌，肿瘤内的异质性可能是调节治疗反应的重要因素。在……里面 特定的、静止的、类似G0的亚群可能会产生对治疗有更强反应的肿瘤 治疗方案并允许在标准护理(SOC)后肿瘤再生长。然而，类似G0的肿瘤种群是 目前定义不明确，即使在单细胞基因组学应用于GBM之后也是如此。我们未能完全理解和理解 对静止/类G0状态进行实验建模代表了一个关键的知识鸿沟，但也是一个关键的机会， 对于胶质瘤和其他癌症，AS中和G0细胞可以有效地防止放化疗抵抗 和肿瘤复发。 这项资助的目的是为GBM肿瘤和G0样状态提供一个功能和分子定义。 他们对SOC的回应。在目标1中，我们将定义管理长期和短期静止的分子网络 使用一种新的G0报告系统结合单细胞基因组分析对GBM患者肿瘤的状态进行研究。 在目标2中，我们将检验休眠的G0GBM细胞具有独特的RNA和染色质特征的假设 是SOC存活和肿瘤再生所必需的。在目标3中，我们将研究并命名NuA4/KAT5赖氨酸 乙酰转移酶复合体作为GBM中G0样态的关键调节因子和候选治疗靶点。 这些目标建立在强大的初步数据基础上，包括：创建一种基于机器学习的方法 胶质瘤中G0样细胞的鉴定、单细胞RNA的整合分析和原代和原代细胞的染色质分析 PDX GBM肿瘤的标准护理，用于识别GBM G0调节因子的功能基因组筛查，以及 GBM肿瘤模型中G0状态功能解剖的实验模型。 如果成功，这项资助将为类GBM G0状态产生一种新的工作模式，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 明确这些人群如何对SOC做出反应，并在复发期间改变肿瘤动力学。最后，它将提供 用于一种新的治疗策略的数据，在该策略中，IV级肿瘤的侵袭性因 在肿瘤细胞中触发延长的或永久的类G0状态。

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.