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Glioblastoma (GBM), the most aggressive primary brain malignancy, consists of diverse cell subpopulations expressing a variety of cell lineage markers. Improvements in GBM therapy and survival require a deeper knowledge of the shifting subpopulations of tumorigenic cells within typical GBMs and their relative vulnerabilities. GBM development is associated with the appearance of highly proliferative tumor cells that lead to a hypoxic, metabolically reprogrammed, immunosuppressive microenvironment that favors tumor progression. In addition, GBM contains self-renewing, tumorigenic cancer stem cells (CSC) that contribute to tumor initiation and therapeutic resistance. Using a combined multicolor immunofluorescent and Hematoxylin and Eosin (H&amp;E) staining approach with archival formalin-fixed, paraffin embedded tissue from primary, recurrent, and autopsy glioblastoma specimens, we have investigated the complex topology of the GBM microenvironment with particular focus on the association and distribution of several important functional and metabolic markers. High-resolution tissue image analysis permitted precise colocalization and quantification of four biomarkers (Ki-67, GLUT1, Nestin, Hif-1a) of the entire specimen image and at the single cell level. Our results demonstrate discrete subpopulations with specific regional localization with respect to blood vessels and to each other. In particular, highly proliferative Nestin-positive cells are preferentially located near blood vessels. These cells do not express GLUT1 and are Hif-1a positive. In contrast, GLUT1-positive cells are negative for Nestin, demonstrate low proliferation, and are preferentially located at the zones of pseudopalisading necrosis, furthest from blood vessels. In addition, GLUT1-positive cells show reduced Hif-1a expression compared to Nestin-positive cells. Our novel approach provides a means to identify, characterize, and monitor the changing nature of GBM before and after various treatment modalities with the ultimate aim of revealing selective vulnerabilities in order to retard or cure this neoplasm.

TMIC-05. GLIOBLASTOMA CONTAINS TOPOLOGICALLY DISTINCT PROLIFERATIVE AND METABOLICALLY DEFINED SUBPOPULATIONS OF NESTIN AND GLUT1-POSITIVE CELLS