Biophysical and molecular dialogue of glioma cells and the brain microenvironment

描述（由申请人提供）：胶质母细胞瘤（GBM）是一种快速生长的高度播散性脑肿瘤，对标准和靶向治疗表现出严重的耐药性。因此，GBM总是具有致死性结局。GBM的侵袭性归因于其内在的基因突变和干细胞样起源。然而，这些遗传畸变和细胞起源促进肿瘤侵袭和治疗抗性的分子机制仍然不清楚。在该提案中，我们提出了这样的假设，即血管龛代表具有不同宿主细胞成分和独特机械性质的微解剖单元，其与颅压升高和高级干细胞样GBM的独特机械表型相一致，促进了这些侵袭性肿瘤的发病机制、复发和治疗抗性。由于高级别GBM经常出现在脑室下区（SVZ），我们集中精力了解来自该区域的GBM的病理。我们将比较和对比我们的分析使用高级别的少突胶质细胞瘤，从更多的定向祖细胞发展，并描绘了一个更好的反应性和更有利的结果比GBM。本申请的主要目的是首先描述血管生态位内不同的血管周围先天免疫细胞，并暗示这些浸润细胞是促进新血管形成和肿瘤干细胞样存活的关键成分，特别是在面对辐射和抗血管治疗时。 第二，测试GBM的独特机械表型和该微环境的升高的颅压和ECM硬度通过透明质酸诱导的糖萼和整合素依赖性张力的修饰促进炎症、新血管形成和GBM分化来促进血管生态位的想法。第三，检验侵袭性GBM的内在机械表型与SVZ定位的GBM的机械特征（压缩、刚度）的治疗诱导的变化一起通过驱动GBM分化以重建血管生态位并促进侵袭性、侵袭性EMT样表型来增强/诱导抗性和肿瘤复发的假设。我们将采取多学科方法，将物理科学的概念和技术与经典的细胞/分子生物学策略融合在一起，以实现我们的目标。我们将采用人类组织和新鲜分离的细胞，原位操作和转基因模型，并将比较高级别GBM的少突胶质细胞瘤的生物学。该提案建立在UCSF的广泛资源基础上，将促进TMEN网络内的跨学科研究。

DESCRIPTION (provided by applicant): Glioblastomas (GBM) are rapidly growing highly disseminated brain tumors that exhibit profound resistance to standard and targets therapies. Consequently GBM invariably have a fatal outcome. The aggressive nature of GBM has been attributed to their intrinsic genetic mutations and stem-like origins. Nevertheless, the molecular mechanisms whereby these genetic aberrations and cellular origins promote tumor invasion and treatment resistance remain ill-defined. In this proposal we pose the hypothesis that the vascular niche represents a micro-anatomical unit with distinct host cell constituents and unique mechano-properties that in concert with elevated cranial pressure and the unique mechano-phenotype of high grade stem cell-like GBM fosters the pathogenesis, recurrence and treatment resistance of these aggressive tumors. Because high grade GBM frequently arise within the subventricular zone (SVZ) we focus our efforts on understanding the pathology of GBM derived from this region. We will compare and contrast our analysis using high-grade oligodendrogliomas which develop from more committed progenitor cells and depict a better responsiveness and more favorable outcome than GBM. The major objectives of this application are first, to delineate the distinct perivascular innate immune cells within the vascular niche and to implicate these infiltrating cells as constituents critical in promoting neovascularization and tumor stem cell like survival, specifically in the face of irradiation and anti-vascular therapies. Second, to test the idea that the unique mechano-phenotype of GBM and the elevated cranial pressure and ECM stiffness of this microenvironment foster the vascular niche by promoting inflammation, neovascularization and GBM differentiation through hyaluronic acid-induced modification of the glycocalyx and integrin-dependent tension. Third, to test the hypothesis that the intrinsic mechano-phenotype of aggressive GBM together with therapy-induced changes in the mechanical features (compression, stiffness) of SVZ-localized GBM enhance/induce resistance and tumor recurrence by driving GBM differentiation to re-establish the vascular niche and promote an aggressive, invasive EMT-like phenotype. We will take a multidisciplinary approach that melds concepts and techniques from the physical sciences with classic cell/molecular biology strategies with clinical input to achieve our goal. We will employ human tissues and freshly isolated cells, orthotopic manipulations and transgenic models and will compare the biology of high grade GBM to that of oligodendrogliomas. The proposal builds upon extensive resources at UCSF and will foster cross-disciplinary research within the TMEN network.