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的脑肿瘤，对标准和靶向治疗表现出深刻的耐药性。因此，GBM总是有致命的后果。GBM的侵袭性归因于其内在的基因突变和茎样起源。然而，这些遗传畸变和细胞起源促进肿瘤侵袭和治疗抵抗的分子机制仍然不明确。在这一建议中，我们提出假设，血管壁龛代表了具有独特宿主细胞成分和独特机械特性的微观解剖单元，与颅压升高和高级别干细胞样GBM的独特机械表型相一致，促进了这些侵袭性肿瘤的发病、复发和治疗抵抗。由于高级别GBM经常发生在心室下区（SVZ），因此我们将重点放在了解源自该区域的GBM的病理上。我们将用高级别少突胶质细胞瘤来比较和对比我们的分析，高级别少突胶质细胞瘤由更稳定的祖细胞发展而来，并描绘出比GBM更好的反应性和更有利的结果。这项应用的主要目的是首先，描绘血管生态位内独特的血管周围固有免疫细胞，并将这些浸润细胞作为促进新生血管和肿瘤干细胞样存活的关键成分，特别是在面对辐射和抗血管治疗时。

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.