权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Chromatin Modifications in GBM-Propagating Cells

GBM 增殖细胞中的染色质修饰

基本信息

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
项目类别：
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

项目摘要

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.

总结/摘要多形性胶质母细胞瘤（GBM）是最常见的脑癌，普遍具有致命性，中位生存期为~ 18个月迫切需要新的治疗方法。GBM在细胞水平上是异质的，肿瘤增殖干细胞样细胞（又名GBM干细胞，GSC）的群体，与GBM生长、治疗抗性和复发不成比例。大量证据表明， GBM细胞具有高度可塑性，并在干细胞样/肿瘤增殖表型之间动态转换以及响应于背景表观遗传事件的更分化/非肿瘤传播表型。阐明参与GSC的产生和维持的表观遗传机制（即GSC的抑制），分化和去分化转录程序的激活）对于理解恶性胶质母细胞瘤的分子基础，并将进一步发展更有效的治疗学我们发现，重编程转录因子Oct 4和Sox 2（Oct 4/Sox 2）通过沉默miRNAs将非GSC表型重编程为肿瘤增殖GSC，协同抑制GSC表型。我们现在假设，靶向（i）非组蛋白DNA结合蛋白HMGA 1，和（ii）多梳阻遏物的组分复合物2（PRC 2）催化组蛋白3 K27三甲基化（H3 K27 me 3），其在细胞凋亡中起重要作用。通过Oct 4/Sox 2产生GSC。该提案的重点是HMGA 1和PRC 2如何协同调节染色质的结构和功能以及基因表达在肿瘤增殖GSC诱导过程中的作用 Oct 4/Sox 2调节的miRNA回路的治疗效果以及测试抑制这些Oct 4/Sox 2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Oct 4/Sox 2抑制的miRNA在 Oct 4/Sox 2上调HMGA 1、PRC 2、H3 K27 me 3和GSC诱导;（2）确定HMGA 1 和H3 K27 me 3响应于Oct 4/Sox 2共调节染色质功能和转录网络;（3）开发新的GBM治疗策略，基于通过以下方法抑制GSC诱导的这些机制： Oct4/Sox 2.这项研究将填补我们理解重编程转录因子如何诱导GSC和GBM增殖。我们将具体确定“结构转录因子” HMGA 1和PRC 2依赖性H3 K27 me 3协同调节GSC诱导的转录组。我们将还评估了使用创新的纳米颗粒治疗靶向这些新型GSC驱动剂的潜力，基础和药物治疗。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Extracellular Matrix Protein Tenascin C Increases Phagocytosis Mediated by CD47 Loss of Function in Glioblastoma.

DOI：
10.1158/0008-5472.can-18-3125
发表时间：
2019-05-15
期刊：
Cancer research
影响因子：
11.2
作者：
Ma D;Liu S;Lal B;Wei S;Wang S;Zhan D;Zhang H;Lee RS;Gao P;Lopez-Bertoni H;Ying M;Li JJ;Laterra J;Wilson MA;Xia S
通讯作者：
Xia S

Monoallelic IDH1 R132H Mutation Mediates Glioma Cell Response to Anticancer Therapies via Induction of Senescence.

DOI：
10.1158/1541-7786.mcr-21-0284
发表时间：
2021-11
期刊：
Molecular cancer research : MCR
影响因子：
0
作者：
Zhan D;Ma D;Wei S;Lal B;Fu Y;Eberhart C;Laterra J;Ying M;Li Y;Meeker A;Lopez-Bertoni H;Xia S
通讯作者：
Xia S

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