GE-38 * IDENTIFYING THE TREATMENT-RESISTANT MESENCHYMAL SIGNATURE BY COMPARATIVE ANALYSES BETWEEN GLIOMA SPHERE-FORMING CELLS AND THEIR GLIOBLASTOMAS OF ORIGIN

Abstract

The mesenchymal (Mes) subtype of glioblastoma (MesGBM) correlates with poor patient prognosis. Surprisingly, agents that target mesenchymal tumors, such as the antiangiogenesis drug bevacizumab, failed to show a benefit in MesGBM. The expression of MesGBM might result from both cells from the surrounding microenvironment or from the tumor cells themselves. We hypothesized that MesGBM driven by Mes-expressing tumor cells would show increased aggressiveness compared to those driven by Mes-expressing stroma. We examined 42 glioma sphere-forming cell (GSCs) lines, derived from fresh surgical specimens, by performing whole transcriptome sequencing, copy number analysis, and whole exome sequencing and compared the GSCs to the tumors from which they were derived. GSCs aggressiveness was determined by in vivo survival of orthotopic xenografted mice and in vitro radiation survival. The TCGA expression subtype of the GSCs and their matched tumor was determined by single sample gene set enrichment analysis (ssGSEA). Of the 15 tumors belonging to the mesenchymal subtype, 4 of the matched GSCs were also mesenchymal (concordant pairs, CP) and the remaining 11 GSCs were either proneural or classical subtypes (discordant pairs, DP). The normalized mesenchymal scores of the 4 CP tumors (mean 0.90, range 0.80-0.98) was higher than those the 11 DP tumors (mean 0.75, range 0.69-0.90). We determined tumor purity based on sequencing data and found it significantly higher in DP tumors than CP, suggesting a stromal contribution to the Mes signature in the DP tumors. In addition, EGFR amplification occurred in 36% of DP tumors, and 0% of TP tumors. CP tumors showed increased radiation resistance and decreased in vivo survival compared to DP tumors. In summary, stromal-driven mesenchymal tumors showed decrease aggressiveness compared to tumor cell-driven MesGBM, suggesting that therapeutics targeting the microenvironment, such as anti-angiogenesis drugs, may have a greater role in tumors where the stromal contribution dominates.