Dissecting the biology and consequence of circulating glioma cells

剖析循环神经胶质瘤细胞的生物学和后果

基本信息

批准号：
10225601
负责人：
JAY FITZGERALD DORSEY
金额：
$ 47.82万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10225601
关键词：
Address Adult Beds Biological Biology Blood Blood Circulation Brain Neoplasms Cell Separation Cell Survival Cells Characteristics Data Detection Development Evaluation Excision Foundations Generations Genetic Genetic Transcription Glioblastoma Glioma Homing Human Individual Infrastructure Intravenous Investigation Kinetics Lead Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mediating Methodology Methods Micrometastasis Modeling Molecular Molecular Target Mus Operative Surgical Procedures Pathogenesis Pathologic Pathway interactions Patients Pattern Pharmacology Phenotype Population Positioning Attribute Primary Brain Neoplasms Primary Neoplasm Property Public Health RNA Radiation Radiation therapy Radio Recurrence Recurrent tumor Relapse Reporting Research Resistance Role Signal Transduction Site Solid Neoplasm Specimen System Testing Therapeutic Transgenic Mice Transgenic Organisms Treatment Efficacy Tumor Biology Tumor-Derived Tumorigenicity Virus WNT Signaling Pathway base cancer stem cell chemotherapy cytotoxic genetic approach genotoxicity improved inhibitor/antagonist innovation knock-down lentivirally transduced mouse model neoplastic cell neuro-oncology new therapeutic target novel novel strategies novel therapeutic intervention pre-clinical single-cell RNA sequencing standard of care stem cells stem-like cell stemness targeted treatment temozolomide therapeutic evaluation treatment strategy tumor tumor growth tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Glioblastoma multiforme (GB) or grade IV glioma, is one of the most lethal human malignancies and the most common malignant primary brain tumor in adults, with a current median survival of only 14 months. Despite aggressive standard-of-care treatments including surgical resection, radiation, and chemotherapy, local recurrence of GB is essentially universal, and recurrent tumors are highly resistant to conventional cytotoxic treatments. New treatment strategies based on an improved understanding of recurrence mechanisms are desperately needed to improve overall survival for these patients. It has been highly suggested that treatment-resistant glioma cells, particularly glioma stem cells (GSCs), i.e., tumor-initiating cells or tumor-propagating cells, contribute to GB recurrence via translocation from parenchymal GSC niches. We propose an intriguing new mechanism whereby glioma cells in circulation can similarly contribute to tumor development/regrowth. Utilizing human specimen and orthotopic, genetic mouse tumor models our preliminary data demonstrate that these circulating glioma cells (CGCs) acquire a cancer stem cell-like phenotype: activated in stemness, resistant to genotoxic treatments, and more importantly, capable of homing to a primary tumor site to repopulate locally and contribute to new tumor formation. This suggests a previously unidentified role of CGCs in tumor micrometastases and local relapse in GB and possibly other solid tumors. We are uniquely positioned (as the first group to report on the identification of circulating glioma cells - CGCs) to extend our investigations to: i) decipher the key molecular features underlying CGC development and the potential contribution of CGCs to tumor bed recurrences, ii) discover novel therapeutic interventions against CGCs to overcome the universal local recurrence patterns seen in GB. Our proposal seeks to accomplish these translationally-relevant objectives through an innovative set of complementary strategies. Based on our preliminary results and expertise of the assembled team, we propose to test the hypothesis that CGCs recapitulate the features of CSCs, contribute to primary tumor reseeding and that molecular targeting of CGCs provide a novel strategy to overcome GB therapy resistance. To test this hypothesis, we propose the following specific aims: AIM 1. Define the potential stem cell features and transcriptional landscape of CGC by performing single cell RNA-seq. AIM 2. Determine the WNT- dependent mechanisms for CGC-mediated GB tumorigenesis. AIM 3. Test the therapeutic efficacy of WNT inhibition in GB tumorigenesis and therapy resistance. By accomplishing these aims via our combined interdisciplinary expertise, infrastructure, and discovery of a novel GB recurrence paradigm, we seek to build the foundation for an improved therapeutic approach for GB.

项目摘要/摘要胶质母细胞瘤多形（GB）或IV级神经胶质瘤是最致命的人类恶性肿瘤之一成人最常见的恶性原发性脑肿瘤，当前的中位存活率仅为 14个月。尽管有积极的护理标准治疗，包括手术切除，辐射和化学疗法，GB的局部复发本质上是普遍的，并且复发性肿瘤具有高度抗性传统的细胞毒性治疗。基于改进的理解的新治疗策略迫切需要复发机制来改善这些患者的总体生存率。它有强烈建议，耐药性神经胶质瘤细胞，特别是神经胶质瘤干细胞（GSC），即通过实质GSC壁ni。我们提出了一种有趣的新机制循环类似地有助于肿瘤发育/再生。利用人类标本和原位，遗传小鼠肿瘤模型我们的初步数据表明这些循环神经胶质瘤细胞（CGC）获得癌症干细胞样表型：在干性中激活，对遗传毒性有抵抗力治疗，更重要的是，能够将原发性肿瘤部位归巢，以便在本地重新填充有助于新的肿瘤形成。这表明CGC在肿瘤中的先前未识别的作用 GB和其他实体瘤中的微型转移和局部复发。我们是独特的位置（作为报告鉴定循环神经胶质瘤细胞-CGCS的第一个组）调查：i）破译CGC开发的关键分子特征和潜力 CGC对肿瘤床复发的贡献，ii）发现针对的新型治疗干预措施 CGC克服GB中看到的通用局部复发模式。我们的建议寻求通过一组创新的补充，实现这些与翻译的目标策略。根据我们的初步结果和组装团队的专业知识，我们建议测试 CGC概括了CSC的特征的假设，有助于原发性肿瘤播种和 CGC的分子靶向提供了一种克服GB治疗抗性的新策略。测试该假设，我们提出以下特定目的：目标1。定义潜在的干细胞特征通过执行单细胞RNA-seq的CGC的转录景观。目标2。确定wnt- CGC介导的GB肿瘤发生的依赖机制。目标3。测试的治疗功效 WNT抑制GB肿瘤发生和耐药性。通过我们实现这些目标跨学科的专业知识，基础设施和发现新颖的GB复发范式的发现，我们寻求为改进GB的治疗方法奠定基础。