Chromatin Modifications in GBM-Propagating Cells

GBM 增殖细胞中的染色质修饰

• 批准号: 10115136
• 负责人: John J Laterra
• 金额: $ 39.95万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115136
• 关键词: Animals; Architecture; Automobile Driving; Binding; Cells; Chromatin; Chromatin Structure; Code; Complement; DNA Binding; DNA-Binding Proteins; Development; Epigenetic Process; Event; Foundations; Gene Expression; Generations; Genetic Transcription; Glioblastoma; Glioma; Goals; Growth; HMGA1 gene; Histones; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Maps; MicroRNAs; Molecular; Oncogenes; Patients; Pharmacology; Phenotype; Play; Polycomb; Population; Primary Brain Neoplasms; Proteins; Recurrence; Regulation; Repression; Repressor Proteins; Research; Role; Structure; Structure-Activity Relationship; Therapeutic; Transcriptional Regulation; Treatment Efficacy; Untranslated RNA; Up-Regulation; Xenograft procedure; base; chromatin modification; combinatorial; design; effective therapy; genome-wide; improved; in vivo; inhibitor/antagonist; innovation; nanoparticle; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; programs; reconstitution; relating to nervous system; response; stem; stem cell biomarkers; stem cells; stem-like cell; stemness; therapeutic development; therapeutic evaluation; therapeutically effective; therapy resistant; transcription factor; transcriptional reprogramming; transcriptome; treatment strategy; tumor; tumor growth

SUMMARY/ABSTRACT Glioblastoma multiforme (GBM), the most common brain cancer, is universally fatal with median survival of ~ 18 months. New therapies are desperately needed. GBM is heterogeneous at the cellular level with small populations of tumor propagating stem-like cells (aka, GBM stem cells, GSCs) that contribute disproportionately to GBM growth, therapeutic resistance and recurrence. Substantial evidence indicates that GBM cells are highly plastic and dynamically transition between the stem-like/tumor propagating phenotype and more differentiated/non-tumor propagating phenotype in response to contextual epigenetic events. Elucidating the epigenetic mechanisms involved in the generation and maintenance of GSCs (i.e. repression of differentiating and activation of dedifferentiation transcriptional programs) is critical to understanding the molecular underpinnings of glioblastoma malignancy and will further the development of more effective therapeutics. We have found that the reprogramming transcription factors Oct4 and Sox2 (Oct4/Sox2) phenotypically reprogram non-GSCs to tumor-propagating GSCs through the silencing of miRNAs that cooperatively inhibit the GSC phenotype. We now hypothesize that the repression of specific miRNAs that target (i) the non-histone DNA-binding protein HMGA1, and (ii) components of the polycomb repressor complex 2 (PRC2) that catalyzes histone3K27 trimethylation (H3K27me3) plays an essential role in the generation of GSCs by Oct4/Sox2. This proposal focuses on how HMGA1 and PRC2 cooperatively regulate chromatin structure and function and gene expression during the induction of tumor propagating GSCs by Oct4/Sox2 and on testing the therapeutic efficacy of inhibiting these Oct4/Sox2-regulated miRNA circuits. These goals will be achieved via three specific aims- (1) Determine the role of Oct4/Sox2-repressed miRNAs in the up-regulation of HMGA1, PRC2, H3K27me3 and GSC induction by Oct4/Sox2; (2) Determine how HMGA1 and H3K27me3 co-regulate chromatin function and transcriptional networks in response to Oct4/Sox2; (3) Develop novel GBM treatment strategies based on inhibiting these mechanism of GSC induction by Oct4/Sox2. This research will fill critical gaps in our understanding of how reprogramming transcriptions factors induce GSCs and GBM propagation. We will specifically identify how the “structural transcription factor” HMGA1 and the PRC2-dependent H3K27me3 cooperate to regulate the GSC-inducing transcriptome. We will also evaluate the potential to therapeutically target these novel GSC-drivers using innovative nanoparticle- based and pharmacologic therapeutics.

摘要/摘要 多形性胶质母细胞瘤 (GBM) 是最常见的脑癌，普遍致命，中位生存期约为 ~ 18 个月，迫切需要新的治疗方法，GBM 在细胞水平上具有异质性。 肿瘤增殖干细胞（又名 GBM 干细胞，GSC）群体 大量证据表明，与 GBM 生长、治疗耐药和复发不成比例。 GBM 细胞具有高度可塑性，并且在干细胞样/肿瘤增殖表型之间动态转变 以及响应背景表观遗传事件的更多分化/非​​肿瘤传播表型。 阐明参与 GSC 生成和维持的表观遗传机制（即抑制 去分化转录程序的分化和激活）对于理解 胶质母细胞瘤恶性肿瘤的分子基础，并将进一步开发更有效的 我们发现重编程转录因子 Oct4 和 Sox2 (Oct4/Sox2) 通过沉默 miRNA，将非 GSCs 表型重编程为肿瘤增殖性 GSCs 我们现在捕获了特定 miRNA 的抑制作用。 目标 (i) 非组蛋白 DNA 结合蛋白 HMGA1，以及 (ii) 多梳阻遏蛋白的成分 催化组蛋白 3K27 三甲基化 (H3K27me3) 的复合物 2 (PRC2) 在 Oct4/Sox2 生成 GSC 该提案重点关注 HMGA1 和 PRC2 如何合作调节。 诱导肿瘤增殖 GSC 过程中的染色质结构和功能以及基因表达 Oct4/Sox2 并测试抑制这些 Oct4/Sox2 调节的 miRNA 回路的治疗效果。 这些目标将通过三个具体目标来实现 - (1) 确定 Oct4/Sox2 抑制的 miRNA 在 Oct4/Sox2 对 HMGA1、PRC2、H3K27me3 和 GSC 诱导的上调 (2) 确定 HMGA1 的作用； 和 H3K27me3 响应 Oct4/Sox2 共同调节染色质功能和转录网络 (3) 基于抑制 GSC 诱导的这些机制，开发新的 GBM 治疗策略 Oct4/Sox2。这项研究将填补我们对重编程转录因子如何理解的关键空白。 我们将具体确定“结构转录因子”如何诱导 GSC 和 GBM 增殖。 HMGA1 和 PRC2 依赖性 H3K27me3 合作调节 GSC 诱导转录组。 还评估了使用创新纳米颗粒治疗靶向这些新型 GSC 驱动因素的潜力 基础和药物治疗。

项目成果

ATRX loss promotes immunosuppressive mechanisms in IDH1 mutant glioma.

ATRX 缺失促进 IDH1 突变神经胶质瘤的免疫抑制机制。

• 发表时间: 2022-06-01
• 影响因子: 15.9
• 作者: Hu, Chengchen;Wang, Kimberly;Damon, Ceylan;Fu, Yi;Ma, Tengjiao;Kratz, Lisa;Lal, Bachchu;Ying, Mingyao;Xia, Shuli;Cahill, Daniel P;Jackson, Christopher M;Lim, Michael;Laterra, John;Li, Yunqing
• 通讯作者: Li, Yunqing

Targeting UDP-α-D-glucose 6-dehydrogenase inhibits glioblastoma growth and migration.

靶向 UDP-α-D-葡萄糖 6-脱氢酶可抑制胶质母细胞瘤的生长和迁移。

• 发表时间: 2018-05
• 影响因子: 8
• 作者: Oyinlade, Olutobi;Wei, Shuang;Lal, Bachchu;Laterra, John;Zhu, Heng;Goodwin, C Rory;Wang, Shuyan;Ma, Ding;Wan, Jun;Xia, Shuli
• 通讯作者: Xia, Shuli

A Sox2:miR-486-5p Axis Regulates Survival of GBM Cells by Inhibiting Tumor Suppressor Networks.

Sox2:miR-486-5p 轴通过抑制肿瘤抑制网络来调节 GBM 细胞的存活。

• 发表时间: 2020
• 影响因子: 11.2
• 作者: Lopez;Kotchetkov, Ivan S;Mihelson, Nicole;Lal, Bachchu;Rui, Yuan;Ames, Heather;Lugo;Guerrero;Quiñones;Green, Jordan J;Laterra, John
• 通讯作者: Laterra, John

Opinion: miRNAs - The new wave of molecular cancer therapeutics.

观点：miRNA——分子癌症治疗的新浪潮。

• 发表时间: 2021-06
• 影响因子: 5
• 作者: Lopez;Laterra, John
• 通讯作者: Laterra, John

Krüppel-like factor 9 and histone deacetylase inhibitors synergistically induce cell death in glioblastoma stem-like cells.

Krüppel 样因子 9 和组蛋白脱乙酰酶抑制剂协同诱导胶质母细胞瘤干细胞样细胞死亡。

• 发表时间: 2018-10-22
• 影响因子: 3.8
• 作者: Tung, Brian;Ma, Ding;Wang, Shuyan;Oyinlade, Olutobi;Laterra, John;Ying, Mingyao;Lv, Sheng;Wei, Shuang;Xia, Shuli
• 通讯作者: Xia, Shuli