Dissecting the biology and consequence of circulating glioma cells

项目总结/摘要 多形性胶质母细胞瘤（Glioblastoma multiforme，GB）又称IV级胶质瘤，是人类最致命的恶性肿瘤之一 是成人中最常见的恶性原发性脑肿瘤，目前的中位生存期仅为 14个月尽管积极的标准护理治疗，包括手术切除，放射治疗， 化疗，局部复发GB基本上是普遍的，复发肿瘤是高度耐药的 传统的细胞毒性治疗。基于更好理解的新治疗策略 迫切需要研究复发机制以提高这些患者的总体生存率。它有 已经高度提示治疗抗性神经胶质瘤细胞，特别是神经胶质瘤干细胞（GSC），即， 肿瘤起始细胞或肿瘤增殖细胞，通过从 实质GSC龛。我们提出了一个有趣的新机制，即胶质瘤细胞在 循环可类似地促进肿瘤发展/再生长。利用人体标本， 原位遗传小鼠肿瘤模型我们的初步数据表明，这些循环胶质瘤 细胞（CGC）获得癌症干细胞样表型：在干细胞中活化，对遗传毒性具有抗性， 治疗，更重要的是，能够归巢到原发性肿瘤部位以在局部重新增殖， 有助于新肿瘤的形成。这表明以前未被识别的CGC在肿瘤中的作用， GB和可能的其他实体瘤中的微转移和局部复发。我们有着独特的优势 (as第一个报告循环胶质瘤细胞（CGC）鉴定的小组）， 研究：i）破译CGC发展的关键分子特征和潜在的 CGC对肿瘤床复发的贡献，ii）发现新的治疗干预， CGC克服了GB中常见的局部复发模式。我们的建议旨在 通过一套创新的互补性的 战略布局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CGC概括了CSC的特征，有助于原发性肿瘤再种植， CGC的分子靶向提供了克服GB治疗抗性的新策略。测试 根据这一假设，我们提出了以下具体目标：目标1。定义潜在的干细胞特征 和转录景观的CGC通过执行单细胞RNA-seq。AIM 2.确定WNT- CGC介导的GB肿瘤发生的依赖机制。AIM 3.测试的治疗效果 WNT抑制GB肿瘤发生和治疗抗性。通过实现这些目标，我们 结合跨学科的专业知识，基础设施，并发现一种新的GB复发模式， 我们寻求为GB的改进治疗方法建立基础。

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.