Abstract
Glioblastoma stem cells (GSC) co-exhibiting a tumor-initiating capacity and a radio-chemoresistant phenotype, are a compelling cell model for explaining tumor recurrence. We have previously characterized patient-derived, treatment-resistant GSC clones (TRGC) that survived radiochemotherapy. Compared to glucose-dependent, treatment-sensitive GSC clones (TSGC), TRGC exhibited reduced glucose dependence that favor the fatty acid oxidation pathway as their energy source. Using comparative genome-wide transcriptome analysis, a series of defense signatures associated with TRGC survival were identified and verified by siRNA-based gene knockdown experiments that led to loss of cell integrity. In this study, we investigate the prognostic value of defense signatures in glioblastoma (GBM) patients using gene expression analysis with Probeset Analyzer (131 GBM) and The Cancer Genome Atlas (TCGA) data, and protein expression with a tissue microarray (50 GBM), yielding the first TRGC-derived prognostic biomarkers for GBM patients. Ribosomal protein S11 (RPS11), RPS20, individually and together, consistently predicted poor survival of newly diagnosed primary GBM tumors when overexpressed at the RNA or protein level [RPS11: Hazard Ratio (HR) = 11.5, p<0.001; RPS20: HR = 4.5, p = 0.03; RPS11+RPS20: HR = 17.99, p = 0.001]. The prognostic significance of RPS11 and RPS20 was further supported by whole tissue section RPS11 immunostaining (27 GBM; HR = 4.05, p = 0.01) and TCGA gene expression data (578 primary GBM; RPS11: HR = 1.19, p = 0.06; RPS20: HR = 1.25, p = 0.02; RPS11+RPS20: HR = 1.43, p = 0.01). Moreover, tumors that exhibited unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) or wild-type isocitrate dehydrogenase 1 (IDH1) were associated with higher RPS11 expression levels [corr (IDH1, RPS11) = 0.64, p = 0.03); [corr (MGMT, RPS11) = 0.52, p = 0.04]. These data indicate that increased expression of RPS11 and RPS20 predicts shorter patient survival. The study also suggests that TRGC are clinically relevant cells that represent resistant tumorigenic clones from patient tumors and that their properties, at least in part, are reflected in poor-prognosis GBM. The screening of TRGC signatures may represent a novel alternative strategy for identifying new prognostic biomarkers.
Highlights
Glioblastoma (GBM) WHO grade IV is the most common and aggressive brain tumor in adults, and currently has no cure
We found 9 markers to be significantly associated with poor prognosis when expression levels were upregulated only in newly diagnosed tumors, while 12 markers were associated with shorter survival when upregulated only in recurrent tumors
The results suggest that treatment-resistant GSC clones (TRGC) are a clinically relevant model of the cell population within a GBM tumor that confers treatment resistance and facilitates development of tumor recurrence
Summary
Glioblastoma (GBM) WHO grade IV is the most common and aggressive brain tumor in adults, and currently has no cure. Temozolomide (TMZ), administered concurrently with and without radiation therapy (RT), is the standard first-line treatment in GBM [1,2,3,4]. Methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter has emerged as an important prognostic and predictive factor for TMZ treatment of newly diagnosed GBM [5]. Bevacizumab, an anti-angiogenic drug, was designed to block vascular endothelial growth factor (VEGFA), and is FDA-approved as the second-line therapy for treating recurrent GBM. While improving progression-free survival, the addition of bevacizumab to RT-TMZ did not improve survival in patients with glioblastoma [7, 8, 9]. Identification of novel treatment targets associated with patient prognosis for GBM remains a highly important goal
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