TMOD-10: Murine avatars permit study of glioblastoma genesis and progression


Aurora Neuroscience Innovation Institute


INTRODUCTION: Murine glioblastoma patient derived xenografts (PDX) hold great promise in the development of personalized, treatments. Additionally, murine avatars present an unparalleled opportunity to understand the mechanisms of GBM initiation, progression, migration and invasion, and resistance to treatment. The quality of the data obtained when using murine avatars is dependent upon the fidelity of the model system; that is, how closely does the PDX reproduce the clinical tumor with respect to molecular and biomarker features, tumor microenvironment, and microanatomical characteristics. We hypothesize that careful attention to location of tissue harvest, tissue handling, and adaptive culture techniques will result in faithful and reproducible avatars.
METHODS: Preoperative MRI diffusion-weighted imaging (DWI) permits localization of the component of the neoplasm with reduced apparent diffusion coefficient (ADC), a surrogate for increased cellularity. The surgical corridor is planned using 3D tractography to develop a trajectory to the this target within the subventricular zone (SVZ) for tissue harvest. Targeted tissue is harvested using a non-ablative suction and mechanical cutting device. Tissue is captured in a closed loop system to minimize atmospheric exposure and degradation. Tissue is maintained at 4 C, and constantly perfused by cold culture media. The tissue is transported to lab and processed into single cell suspension for subsequent sphere and laminin culture and ortho- and hetero-topic patient derived xenograft.
RESULTS: Viable orthotopic GBM PDXs recapitulated histological and molecular features of the parent tumor. Specifically, migration away from the SVZ along white matter tracts was demonstrated. CONCLUSION: Preoperative identification of targets for tissue harvest and mindful maintenance of the tumor microenvironment throughout the collection and processing steps yields PDX that are highly reflective of the original tumor in regards to molecular and anatomical characteristics. This is critical when using murine avatars to develop treatments for and an understanding of the biology of GBM.

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