Project description:Aims: We explore the role of elevated O2-:H2O2 ratio as a prosurvival signal in glioma-propagating cells (GPCs). We hypothesize that depleting this ratio sensitizes GPCs to apoptotic triggers. Results: We observed that elevated O2-:H2O2 ratio conferred enhanced resistance in GPCs, and depletion of this ratio by pharmacological and genetic methods sensitized cells to apopotic triggers. We established the ROS Index as a quantitative measure of normalized O2-:H2O2 ratio and determined its utility in predicting chemosensitivity. Importantly, mice implanted with GPCs of reduced ROS Index demonstrated extended survival. Analysis of tumor sections revealed effective targeting of CD133- and nestin-expressing neural precursors. Furthermore, we established the Connectivity Map to interrogate a gene signature derived from varied ROS Index for patterns of association with individual patient gene expression in 2 clinical databases. We showed that patients with reduced ROS Index demonstrate better survival. These data provide clinical evidence for the viability of our O2-:H2O2-mediated chemosensitivity profiles. Innovation and Conclusion: Gliomas are notoriously recurrent and highly infiltrative, and have been shown to arise from stem-like cells. We implicate elevated O2-:H2O2 ratio as a prosurvival signal in GPC self-renewal and proliferation. The ROS Index provides quantification of O2-:H2O2-mediated chemosensitivity, an advancement in a previously qualitative field. Intriguingly, glioma patients with reduced ROS Index correlate with longer survival and the Proneural molecular classification, a feature frequently associated with tumors of better prognosis. These data emphasize the feasibility of manipulating the O2-:H2O2 ratio as a therapeutic strategy. Total RNA from primary neurosphere culture of brain tumor specimens treated with DPI and DDC as well as non-treated CD133+ and CD133- fractions were compared. Specimens were obtained from 3 patients and replicate arrays were performed for all 3 neurosphere cultures.

Project description:Oligodendrogliomas are defined by IDH-mutations and codeletions of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 23 IDH-mutant oligosarcomas forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 11 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dens network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA, and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas than for grade 3 oligodendrogliomas and comparable to that of grade 4 IDH-mutant astrocytomas. These results establish oligosarcoma as a distinct type of IDH-mutant glioma differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. Diagnosis can be based on the characteristic DNA methylation profile or the combined evidence of sarcomatous histology, IDH-mutation and an oligodendroglioma-typical molecular alteration as TERT promoter mutation and/or 1p/19q codeletion.

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Stem-like glioma-propagating cells contribute to molecular heterogeneity and survival outcome in oligodendroglial tumors

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