Abstract
BackgroundGlioma stem cells (GSCs) are a subpopulation of stem-like cells that contribute to glioblastoma (GBM) aggressiveness, recurrence, and resistance to radiation and chemotherapy. Therapeutically targeting the GSC population may improve patient survival, but unique vulnerabilities need to be identified.ResultsWe isolate GSCs from well-characterized GBM patient-derived xenografts (PDX), characterize their stemness properties using immunofluorescence staining, profile their epigenome including 5mC, 5hmC, 5fC/5caC, and two enhancer marks, and define their transcriptome. Fetal brain-derived neural stem/progenitor cells are used as a comparison to define potential unique and common molecular features between these different brain-derived cells with stem properties. Our integrative study reveals that abnormal expression of ten-eleven-translocation (TET) family members correlates with global levels of 5mC and 5fC/5caC and may be responsible for the distinct levels of these marks between glioma and neural stem cells. Heterogenous transcriptome and epigenome signatures among GSCs converge on several genes and pathways, including DNA damage response and cell proliferation, which are highly correlated with TET expression. Distinct enhancer landscapes are also strongly associated with differential gene regulation between glioma and neural stem cells; they exhibit unique co-localization patterns with DNA epigenetic mark switching events. Upon differentiation, glioma and neural stem cells exhibit distinct responses with regard to TET expression and DNA mark changes in the genome and GSCs fail to properly remodel their epigenome.ConclusionsOur integrative epigenomic and transcriptomic characterization reveals fundamentally distinct yet potentially targetable biologic features of GSCs that result from their distinct epigenomic landscapes.
Highlights
Glioma stem cells (GSCs) are a subpopulation of stem-like cells that contribute to glioblastoma (GBM) aggressiveness, recurrence, and resistance to radiation and chemotherapy
Twelve GSC lines containing a high proportion of stem marker-positive and lineage markernegative cells were used for further molecular analyses (Fig. 1c, Additional file 1: Table S2)
We examined relationships between expression of stem/lineage markers and DNMT/TET expression during GSC differentiation, and observe three clusters of positive correlation, including DNMT3A correlating with OLIG2, SALL2, NESTIN, and TUBB3, and TET1/TET2 correlating with stem markers POU3F2 and SOX2, and lineage marker GFAP
Summary
Glioma stem cells (GSCs) are a subpopulation of stem-like cells that contribute to glioblastoma (GBM) aggressiveness, recurrence, and resistance to radiation and chemotherapy. Glioblastoma (GBM) is the most common and malignant glioma subtype in adults [1]. Average survival is only about 15 months, making GBM one of the most aggressive cancers. It has been hypothesized that distinct subpopulations with a survival advantage and enhanced resistance to therapy are contained within the bulk tumor, yet this property is not readily unveiled by gross histopathologic examination. Genetic and transcriptomic studies have subtyped GBM based on expression profiling into classical, mesenchymal, Theories underlying tumor evolution support the marked heterogeneity observed within individual gliomas. The cancer stem cell (CSC) theory postulates existence of a subpopulation of tumor cells residing at the apex of the hierarchy, propagating tumor formation in a hierarchical manner.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
