Shared mechanisms of astrocyte maturation in development and glioblastoma

星形胶质细胞成熟与胶质母细胞瘤的共同机制

• 批准号: 10494118
• 负责人: Steven A Sloan
• 金额: $ 39.21万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10494118
• 关键词: 3-Dimensional; ATAC-seq; Address; Adult; Affect; Astrocytes; Attenuated; Automobile Driving; Biological; Biological Assay; Biological Models; Brain; Cells; ChIP-seq; Characteristics; Chromatin; DNA Binding; Data; Development; Engineering; Excision; Exhibits; Fetal Development; Genetic Transcription; Genomics; Glioblastoma; Gliomagenesis; Growth; Heterogeneity; Human; Human Development; In Vitro; Individual; Knock-out; Literature; Malignant Neoplasms; Maps; Modeling; Molecular; Mutation; Neuroglia; Neurons; Nuclear; Operative Surgical Procedures; Organoids; Phagocytosis; Population; Primary Brain Neoplasms; Process; Protocols documentation; Scheme; Severity of illness; Shapes; System; Testing; Work; XCL1 gene; cell behavior; cell type; curative treatments; driver mutation; epigenomics; experimental study; fetal; induced pluripotent stem cell; malignant neurologic neoplasms; neoplastic cell; novel; overexpression; postnatal human; progenitor; programs; stem cells; temporal measurement; therapy resistant; three dimensional cell culture; transcription factor; transcriptome sequencing; transcriptomics; tumor

Project Summary Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults. Recent work continues to support the idea that this cancer (like many others) echoes the proliferation and differentiation programs from earlier developmental stages. The possibility that neurological cancers like GBM are essentially `locked in' to a developmental program and retain the controls that instruct these cell populations during development opens new and exciting opportunities. Furthermore, it places an emphasis on the need to identify the molecular triggers that govern the transition of immature progenitor cells to quiescent mature astrocytes during development. In this project we will test the hypothesis that master transcriptional regulators are sufficient for driving astrocyte maturation and that these factors can be used to jump-start stalled maturation within GBM-astrocytes. The ability of individual or small groups of transcription factors to drive cell fate or maturation changes has been demonstrated in a variety of cell types, including neurons and glia. To begin, we used existing transcriptomic, epigenomic, and DNA-binding data to identify a targeted set of candidate transcription factors that we hypothesize catalyze the astrocyte maturation process. We will test whether these transcription factors are capable of inducing precocious maturation in immature human astrocytes by manipulating their expression using schemes that mirror their developmental activity. As a model system, we are using human iPSC-derived cortical organoids, which provides a multicellular platform in which astrogenesis and maturation occurs endogenously along a timescale analogous to what is observed in the fetal and early postnatal human brain. We will also ask how the developmental trajectory of astrocyte maturation is perturbed in the setting of GBM by comparing epigenomic profiles of maturing human astrocytes from the organoid system with single cell data from surgical GBM resections. This comparison will place GBM-astrocyte differentiation in the context of the normal developmental trajectory and reveal potential transcription factors whose absence may contribute to stalled maturation. An important possibility in the pathobiology of gliomagenesis is that the heterogeneous mutations accumulated within GBM-astrocytes render them unreceptive to maturation-inducing transcription factors. Thus, in a final set of experiments, we will use isogenic iPSC lines harboring driver GBM mutations to test their influence on the receptivity to maturation-inducing transcription factors. Together, these studies will help teach us how and where GBM cells are stalled in their developmental programs and offer novel avenues to pursue differentiation schemes to mitigate these deadly tumors.

项目概要 胶质母细胞瘤（GBM）是成人中最常见和最致命的原发性脑肿瘤。近期工作继续 支持这样的观点，即这种癌症（像许多其他癌症一样）与来自的增殖和分化程序相呼应 早期发育阶段。像 GBM 这样的神经系统癌症本质上“锁定”在 发育程序并保留在发育过程中指导这些细胞群的控制打开 新的、令人兴奋的机会。此外，它强调需要识别分子触发因素 在发育过程中控制未成熟祖细胞向静止成熟星形胶质细胞的转变。 在这个项目中，我们将测试主转录调节因子足以驱动星形胶质细胞的假设 这些因子可用于启动 GBM 星形胶质细胞内停滞的成熟。能力 驱动细胞命运或成熟变化的个体或小组转录因子已被 在多种细胞类型中得到证实，包括神经元和神经胶质细胞。首先，我们使用现有的转录组， 表观基因组和 DNA 结合数据，用于识别一组目标候选转录因子 假设催化星形胶质细胞成熟过程。我们将测试这些转录因子是否 能够通过使用操纵其表达来诱导未成熟的人星形胶质细胞早熟 反映他们发展活动的计划。作为模型系统，我们使用人类 iPSC 衍生的皮质 类器官，提供了一个多细胞平台，其中星形发生和成熟是内源性发生的 沿着类似于在胎儿和出生后早期人类大脑中观察到的时间尺度。 我们还将询问在 GBM 的情况下星形胶质细胞成熟的发育轨迹如何受到干扰 将来自类器官系统的成熟人类星形胶质细胞的表观基因组图谱与来自的单细胞数据进行比较 手术 GBM 切除术。这种比较将把 GBM-星形胶质细胞分化置于正常的背景下 发育轨迹并揭示潜在的转录因子，其缺失可能导致停滞 成熟。胶质瘤发生病理学中的一个重要可能性是异质突变 GBM 星形胶质细胞内的积累使它们无法接受成熟诱导转录因子。因此， 在最后一组实验中，我们将使用含有驱动 GBM 突变的同基因 iPSC 系来测试其影响 对成熟诱导转录因子的接受性。总之，这些研究将帮助我们了解如何以及 GBM 细胞在其发育程序中陷入停滞，并提供了追求分化的新途径 减轻这些致命肿瘤的计划。