Abstract
Glioblastoma (GBM) contains diverse microenvironments with uneven distributions of oncogenic alterations and signaling networks. The diffusely infiltrative properties of GBM result in residual tumor at neurosurgical resection margins, representing the source of relapse in nearly all cases and suggesting that therapeutic efforts should be focused there. To identify signaling networks and potential druggable targets across tumor microenvironments (TMEs), we utilized 5-ALA fluorescence-guided neurosurgical resection and sampling, followed by proteomic analysis of specific TMEs. Reverse phase protein array (RPPA) was performed on 205 proteins isolated from the tumor margin, tumor bulk, and perinecrotic regions of 13 previously untreated, clinically-annotated and genetically-defined high grade gliomas. Differential protein and pathway signatures were established and then validated using western blotting, immunohistochemistry, and comparable TCGA RPPA datasets. We identified 37 proteins differentially expressed across high-grade glioma TMEs. We demonstrate that tumor margins were characterized by pro-survival and anti-apoptotic proteins, whereas perinecrotic regions were enriched for pro-coagulant and DNA damage response proteins. In both our patient cohort and TCGA cases, the data suggest that TMEs possess distinct protein expression profiles that are biologically and therapeutically relevant.
Highlights
Diversity of GBM, there is an uneven distribution of oncogenic events and signaling networks[8,9,10,11,12,13]
Previous studies, including our own, have demonstrated that red-violet fluorescence is absent in the region of central necrosis; that areas of strong 5-aminolevulinic acid (5-Aminolevulinic Acid (ALA)) fluorescence intensity and intraoperative spectroscopic signal correspond to high-density, proliferating bulk tumor (BT) cells; and that weak fluorescence intensity and intraoperative spectroscopic signal correspond to infiltrating tumor margin (TM) tissue
The present study demonstrates that neurosurgical sampling of high-grade glioma guided by differential 5-ALA induced fluorescence is capable of identifying specific tumor microenvironments (TMEs) with distinctive protein expression patterns that correlate with the histopathologic features of these regions[19]
Summary
Diversity of GBM, there is an uneven distribution of oncogenic events and signaling networks[8,9,10,11,12,13]. Previous studies, including our own, have demonstrated that red-violet fluorescence is absent in the region of central necrosis; that areas of strong 5-ALA fluorescence intensity and intraoperative spectroscopic signal correspond to high-density, proliferating BT cells; and that weak fluorescence intensity and intraoperative spectroscopic signal correspond to infiltrating TM tissue. These features allow for the real-time intraoperative distinction of PN, BT, and TM tissue[16,18,19,20,21,22,23]. We report on the differentially expressed proteins and signaling networks across the GBM TMEs, including the pro-survival and anti-apoptotic networks at the infiltrative margins that could represent targets of therapy
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