TMOD-06. CLONAL DYNAMICS OF HUMAN GLIOBLASTOMA IN RESPONSE TO CHEMORADIOTHERAPY
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Abstract Despite aggressive multimodal therapy, human glioblastoma (hGBM), a highly malignant grade IV astrocytic tumour, remains incurable and inevitably relapses. Recent data has implicated intratumoral heterogeneity as the driver of therapy resistance and tumour relapse in hGBM. Thus models that capture the evolution of hGBM biology in response to chemoradiotherapy will allow for the identification of cellular mechanisms that govern GBM therapy failure. In this study, we coupled cellular DNA barcoding technology with our novel in vitro and in vivo chemoradiotherapy model to profile the clonal evolution of hGBM brain tumour initiating cells (BTIC) through therapy. We report the successful barcoding of primary treatment-naive hGBM BTICs at single cell resolution that were then expanded into clonal populations with 40-60x representation per barcode. We then subjected our barcoded cells to in vitro chemoradiotherapy as well as intracranially engrafted barcoded cells into immune-deficient mice for subsequent delivery of in vivo therapy to identify differential barcode selection in two therapy models. Through this, we determined if the same cellular subpopulation is therapy-resistant in vitro and in vivo and whether a pre-existing or a therapy-driven subpopulation(s) seeds hGBM tumour relapse. Profiling the dynamic nature of heterogeneous hGBM subpopulations through disease progression and treatment may lead to identification of the mode(s) of therapy resistance utilized by hGBM which may drive relapse.
