Mechanisms of SOX2 Regulation in Glioblastoma

SOX2 在胶质母细胞瘤中的调控机制

基本信息

批准号：
10504032
负责人：
Albert Hong-Jae Kim
金额：
$ 37.64万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10504032
关键词：
Adult Aftercare Behavior Binding Biological Models Biology Blood - brain barrier anatomy Brain Neoplasms CRISPR/Cas technology Cells ChIP-seq Chemotherapy and/or radiation Chromatin Clinical Collaborations DNA DNA Sequence Alteration Data Disease Engineering Epigenetic Process Failure Gene Expression Gene Targeting Genes Genetic Genetic Heterogeneity Genetic Transcription Genomics Glioblastoma Goals Heterogeneity Human In Vitro Investigation Knowledge Laboratories Lead Libraries Ligase Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mediating Medicine Molecular Oncogenic Operative Surgical Procedures Patients Phenotype Play Post-Translational Regulation Primary Brain Neoplasms Process Prognosis Proteins Publishing RNA Interference Radiation therapy Recurrence Regulation Resistance Role Signal Transduction System Technology Testing Therapeutic Therapeutic Intervention Tumor-Derived Tumorigenicity Ubiquitin Ubiquitination Universities Variant Washington Work base cancer cell cell type chemoradiation clinically relevant effective therapy gain of function human model human stem cells in vivo insight loss of function malignant phenotype multicatalytic endopeptidase complex mutant neoplastic cell nerve stem cell new therapeutic target novel overexpression pluripotency programs promoter self-renewal sex standard of care stem cell biology stem cell model stem cell self renewal stem cells therapeutic target therapy resistant transcription factor transcriptome treatment response tumor tumor growth tumor heterogeneity ubiquitin-protein ligase virtual

项目摘要

ABSTRACT Glioblastoma (GB), the most common malignant primary brain tumor in adults, is invariably fatal. Thus, there is an urgent need to discover new and meaningful therapeutic strategies for this lethal disease. A major reason for our current lack of effective therapies is the extensive genetic and epigenetic heterogeneity of GB tumors. Within the epigenetic diversity of GB cells, accumulating evidence has now firmly established the existence of a clinically important subpopulation of GB cancer cells, called GB stem cells (GSCs), which represents a key cellular substrate for treatment resistance and disease recurrence. Thus, targeting the GSC pool in tumors is an important conceptual strategy, which has the potential to generate novel, durable treatments. We and others have previously shown that the pluripotency-related transcription factor SOX2 plays a critical role in the expression of malignant GSC phenotypes, including self-renewal capacity, invasiveness, and in vivo tumor growth. Remarkably, despite the significant genetic heterogeneity between tumors, SOX2 is expressed in almost all GB tumor cells, including GSCs, implicating this transcription factor as a common epigenetic driver in GB. Thus, the identification of the mechanisms that regulate SOX2 function in GSCs will not only advance our knowledge about the fundamental biology of SOX2 in the clinically relevant GSC subpopulation but also lead to the discovery of SOX2-dependent therapeutic targets that may be effective across different GB tumors and cell types. Based on published work and preliminary data, we will examine two key mechanisms controlling the SOX2 program in GSCs: post-translational control of SOX2 stability (Aim 1) and specification of SOX2 target gene expression through local and long-range chromatin interactions (Aim 2). To study these mechanisms, we will take advantage of two complementary human model systems: a well-characterized library of patient tumor- derived GSCs and a novel, isogenic, human neural stem cell-based GSC model with defined genetic mutations. The long-term goal of this project is to develop novel SOX2-directed therapeutic strategies to disrupt malignant tumor growth and amplify the efficacy of current treatments.

抽象的胶质母细胞瘤（GB）是成人最常见的恶性原发性脑肿瘤，总是致命的。因此，有迫切需要发现这种致命疾病的新的和有意义的治疗策略。主要原因我们目前缺乏有效的疗法是GB肿瘤的广泛遗传和表观遗传异质性。之内 GB细胞的表观遗传多样性，积累的证据现已牢固地确定了临床上的存在 GB癌细胞的重要亚群，称为GB干细胞（GSC），代表钥匙细胞抗治疗性和疾病复发的底物。因此，针对肿瘤中的GSC池是重要的概念策略，有可能产生新颖，耐用的治疗方法。我们和其他人以前已经表明，多能相关的转录因子SOX2在恶性GSC表型的表达，包括自我更新能力，侵入性和体内肿瘤生长。值得注意的是，尽管肿瘤之间存在明显的遗传异质性，但Sox2几乎表达所有GB肿瘤细胞，包括GSC，都将这种转录因子视为GB中常见的表观遗传驱动因素。因此，识别调节SOX2在GSC中功能的机制不仅会推进我们的关于临床相关的GSC亚群中SOX2基本生物学的知识，但也导致在不同的GB肿瘤和细胞中可能有效的SOX2依赖性治疗靶标的发现类型。根据已发表的工作和初步数据，我们将研究控制SOX2的两个关键机制 GSC中的程序：SOX2稳定性的翻译后控制（AIM 1）和SOX2目标基因的规范通过局部和远程染色质相互作用表达（AIM 2）。为了研究这些机制，我们将利用两个互补的人类模型系统：一个良好的患者肿瘤库 - 衍生的GSC和具有定义的基因突变的新型，等源性的，人类干细胞的GSC模型。该项目的长期目标是开发新颖的SOX2定向治疗策略以破坏恶性肿瘤肿瘤生长并扩增当前治疗的功效。