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.
The prognosis for patients with glioblastoma remains poor, so that it is critical that new therapies be developed. This proposal outlines a program that integrates the physical sciences with basic and clinical cancer biology concepts and strategies to explore the role of intrinsic and external force of the vascular niche and stem cell origin of aggressive GBM. The work should yield a new mechano-paradigm with which to understand this disease and identify new avenues to develop novel diagnostics and therapies for GBM.
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