Dissecting the biology and consequence of circulating glioma cells

项目摘要/摘要 多形性胶质母细胞瘤(GB)或IV级胶质瘤是人类最致命的恶性肿瘤之一 和成人最常见的恶性原发脑瘤，目前中位生存期仅为 14个月。尽管有积极的标准护理治疗，包括手术切除，放射治疗和 化疗后，GB的局部复发基本上是普遍的，而复发的肿瘤具有高度的耐药性 传统的细胞毒疗法。基于更好的理解的新治疗策略 迫切需要复发机制来提高这些患者的总体存活率。它有 高度建议耐药的胶质瘤细胞，特别是胶质瘤干细胞(GSCs)，即， 肿瘤启动细胞或肿瘤增殖细胞通过易位促进GB复发 实质性的GSC壁龛。我们提出了一种有趣的新机制，即胶质瘤细胞在 血液循环同样可以促进肿瘤的发展/再生长。利用人体标本和 原位遗传小鼠肿瘤模型我们的初步数据表明，这些循环中的胶质瘤 细胞(CGCs)获得一种肿瘤干细胞样表型：干性激活，对遗传毒性具有抵抗力 治疗，更重要的是，能够定位到原发肿瘤部位，以在当地和 有助于形成新的肿瘤。这表明CGCs在肿瘤中的作用以前并不明确。 GB和可能的其他实体瘤的微转移和局部复发。我们处于独特的位置 (作为第一个报告循环胶质瘤细胞-CGCs鉴定的小组)扩大我们的 研究：i)破译CGC发育的关键分子特征和潜在的 CGCs在肿瘤床复发中的作用，II)发现新的治疗干预措施 CGCS以克服GB中普遍存在的局部复发模式。我们的建议旨在 通过一套创新的互补方案实现这些翻译相关目标 战略。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 假设CGCs概括了CSCs的特征，有助于原发肿瘤的再种植和 CGCs的分子靶向为克服GB耐药提供了一种新的策略。为了测试 在这一假设中，我们提出了以下具体目标：目标1.定义潜在的干细胞特征 通过进行单细胞RNA序列分析，获得CGC的转录图谱。目标2.确定WNT- CGC介导的GB肿瘤发生的相关机制。目的3.检验黄连胶囊的治疗效果 WNT抑制银屑病的发生和耐药。通过我们的 结合跨学科的专业知识、基础设施和发现新的GB复发范例， 我们寻求为改进GB的治疗方法奠定基础。

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.