Biophysical and molecular dialogue of glioma cells and the brain microenvironment

描述(申请人提供)：胶质母细胞瘤(GBM)是一种生长迅速、高度播散性的脑肿瘤，对标准和靶向治疗表现出极大的抵抗力。因此，GBM总是有一个致命的结果。GBM的侵袭性被归因于其固有的基因突变和类似干细胞的起源。然而，这些遗传异常和细胞起源促进肿瘤侵袭和治疗耐药的分子机制仍然不清楚。在这一建议中，我们提出假设，血管龛代表着一个具有不同宿主细胞成分和独特机械特性的微观解剖单位，与高颅压相一致，高级别干细胞样基底膜的独特机械表型促进了这些侵袭性肿瘤的发病、复发和治疗耐药。由于高级别基底膜常发生在脑室下区(SVZ)，因此我们致力于了解起源于该区域的基底膜的病理机制。我们将使用高级别少突胶质细胞瘤来比较和对比我们的分析，这些少突胶质细胞瘤是从更坚定的前体细胞发展而来的，并描绘了比GBM更好的反应性和更有利的结果。这一应用的主要目的是首先，描述血管壁龛内独特的血管周围天然免疫细胞，并将这些浸润性细胞作为促进新生血管和肿瘤干细胞样存活的关键成分，特别是在面对放射和抗血管治疗时。 第二，验证这种微环境独特的机械表型以及升高的颅压和ECM硬度通过透明质酸诱导的糖基化修饰和整合素依赖的张力促进炎症、新生血管和基底膜分化来促进血管生态位的想法。第三，验证侵袭性GBM的内在机械表型和治疗诱导的SVZ定位的GBM力学特征(压缩、僵硬)的改变通过驱动GBM的分化来增强/诱导抵抗和肿瘤复发的假说，以重建血管生态位并促进侵袭性、侵袭性的EMT样表型。我们将采取多学科的方法，将物理科学的概念和技术与经典的细胞/分子生物学策略和临床投入相结合，以实现我们的目标。我们将使用人类组织和新鲜分离的细胞、原位操作和转基因模型，并将高级别GBM的生物学与少突胶质细胞瘤的生物学进行比较。该提案建立在加州大学旧金山分校的广泛资源基础上，并将促进TMAN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.