Clonal variation in drug and radiation response among glioma-initiating cells is linked to proneural-mesenchymal transition
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE89401 | GEO | 2016/12/13
SECONDARY ACCESSION(S): PRJNA352063
REPOSITORIES: GEO
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Project description:Intra-tumor heterogeneity is a hallmark of glioblastoma multiforme, and thought to negatively affect treatment efficacy. Here we establish libraries of glioma-initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability between clones, including a wide range of responses to radiation and drugs. This widespread variability was observed as a continuum of multitherapy resistance phenotypes linked to a proneural-to-mesenchymal shift in the transcriptome.
2016-12-13 | GSE89398 | GEO
Project description:Intra-tumor heterogeneity is a hallmark of glioblastoma multiforme, and thought to negatively affect treatment efficacy. Here we establish libraries of glioma-initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability between clones, including a wide range of responses to radiation and drugs. This widespread variability was observed as a continuum of multitherapy resistance phenotypes linked to a proneural-to-mesenchymal shift in the transcriptome.
2016-12-13 | GSE89400 | GEO
Project description:Intra-tumor heterogeneity is a hallmark of glioblastoma multiforme, and thought to negatively affect treatment efficacy. Here we establish libraries of glioma-initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability between clones, including a wide range of responses to radiation and drugs. This widespread variability was observed as a continuum of multitherapy resistance phenotypes linked to a proneural-to-mesenchymal shift in the transcriptome.
2016-12-13 | GSE89399 | GEO
Project description:Clonal variation in drug and radiation response among glioma-initiating cells is linked to proneural-mesenchymal transition
| PRJNA352063 | ENA
Project description:Glioblastoma is the most common adult primary brain tumor and has a dismal median survival. Radiation is a mainstay of treatment and significantly improves survival, yet recurrence is nearly inevitable. Better understanding the radiation response of glioblastoma will help improve strategies to treat this devastating disease. Here, we present a comprehensive study of the in vivo radiation response of glioma cells in a mouse model of proneural glioblastoma. These tumors are a heterogeneous mix of cell types with differing radiation sensitivities. To explicitly study the gene expression changes comprising the radiation response of the Olig2(+) tumor bulk cells, we used translating ribosome affinity purification (TRAP) from Olig2-TRAP transgenic mice. Comparing both ribosome-associated and total pools of mRNA isolated from Olig2(+) cells indicated that the in vivo gene expression response to radiation occurs primarily at the total transcript level. Genes related to apoptosis and cell growth were significantly altered. p53 and E2F were implicated as major regulators of the radiation response, with p53 activity needed for the largest gene expression changes after radiation. Additionally, radiation induced a marked shift away from a proneural expression pattern toward a mesenchymal one. This shift occurs in Olig2(+) cells within hours and in multiple genetic backgrounds. Targets for Stat3 and CEBPB, which have been suggested to be master regulators of a mesenchymal shift, were also up-regulated by radiation. These data provide a systematic description of the events following radiation and may be of use in identifying biological processes that promote glioma radioresistance.
| S-EPMC3986190 | biostudies-literature
Project description:SUMMARY Despite numerous genome-wide association studies involving glioblastoma (GBM), few therapeutic targets have been identified for this disease. Using patient derived glioma sphere cultures (GSCs), we have found that a subset of the proneural (PN) GSCs undergo transition to a mesenchymal (MES) state in a TNFa/NFkB dependent manner with an associated enrichment of CD44 sub-populations and radio-resistant phenotypes. To the contrary, MES GSCs exhibit constitutive NFkB activation, CD44 enrichment and radio-resistance. Patients whose tumors exhibit a higher MES metagene, increased expression of CD44, or activated NFkB were associated with poor radiation response and shorter survival. Our results indicate that NFkB activation mediated MES differentiation and radiation resistance presents an attractive therapeutic target for GBM. SIGNIFICANCE In this study, we show plasticity between the proneural (PN) and mesenchymal (MES) transcriptome signatures observed in glioblastoma (GBM). Specifically, we show that PN glioma sphere cultures (GSCs) can be induced to a MES state with an associated enrichment of CD44 expressing cells and a gain of radio-resistance, which we implicate as NFkB- dependent. Newly diagnosed GBM samples show a direct correlation between radiation response, higher MES metagene, CD44 expression, and NFkB activation. This correlation is also observed in the subset of GBM samples that do not exhibit IDH1 mutation, a favorable prognostic marker. Our results uncover a previously unknown link between subtype plasticity that is regulated by NFkB. Inhibition of NFkB activation can directly impact radio-resistance and presents an attractive therapeutic target for GBM. Gene expression data for 17 isolated Glioma Stem Cells
| S-ECPF-GEOD-49161 | biostudies-other
Project description:SUMMARY Despite numerous genome-wide association studies involving glioblastoma (GBM), few therapeutic targets have been identified for this disease. Using patient derived glioma sphere cultures (GSCs), we have found that a subset of the proneural (PN) GSCs undergo transition to a mesenchymal (MES) state in a TNFa/NFkB dependent manner with an associated enrichment of CD44 sub-populations and radio-resistant phenotypes. To the contrary, MES GSCs exhibit constitutive NFkB activation, CD44 enrichment and radio-resistance. Patients whose tumors exhibit a higher MES metagene, increased expression of CD44, or activated NFkB were associated with poor radiation response and shorter survival. Our results indicate that NFkB activation mediated MES differentiation and radiation resistance presents an attractive therapeutic target for GBM. SIGNIFICANCE In this study, we show plasticity between the proneural (PN) and mesenchymal (MES) transcriptome signatures observed in glioblastoma (GBM). Specifically, we show that PN glioma sphere cultures (GSCs) can be induced to a MES state with an associated enrichment of CD44 expressing cells and a gain of radio-resistance, which we implicate as NFkB- dependent. Newly diagnosed GBM samples show a direct correlation between radiation response, higher MES metagene, CD44 expression, and NFkB activation. This correlation is also observed in the subset of GBM samples that do not exhibit IDH1 mutation, a favorable prognostic marker. Our results uncover a previously unknown link between subtype plasticity that is regulated by NFkB. Inhibition of NFkB activation can directly impact radio-resistance and presents an attractive therapeutic target for GBM. 4 treatments
| S-ECPF-GEOD-49162 | biostudies-other
Project description:Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Previously we identified and characterized two mutually exclusive GSC subtypes with distinct activated signaling pathways and biological phenotypes. One GSC subtype presented with a gene signature resembling Proneural (PN) HGG, whereas the other was similar to Mesenchymal (Mes) HGG. Classical HGG-derived GSCs were sub-classified as either one of these two subtypes. Differential mRNA expression analysis of PN and Mes GSCs identified 5,796 differentially expressed genes, revealing a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. Expression of ALDH1A3 - one of the most up-regulated Mes representative genes and a universal cancer stem cell marker in non-brain cancers - was associated with self-renewal and a multi-potent stem cell population in Mes but not PN samples. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs in vitro. Lastly, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs in vitro. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3-mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature. Here, we describe the gene expression analysis, including pre-processing methods for the data published by Mao and colleagues in PNAS [1], integration of microarray data from this study with The Cancer Genome Atlas (TCGA) glioblastoma data and also with another published study.
| S-EPMC4523279 | biostudies-literature
Project description:Background: Glioma stem cells (GSCs) are a key factor in glioblastoma (GBM) development and treatment resistance. GSCs can be divided into the mesenchymal (MES) and proneural (PN) subtypes, and these two subtypes of GSCs can undergo interconversion under certain conditions. MES GSCs have higher malignancy and radioresistance and are closely associated with an immunosuppressive microenvironment. Long noncoding RNAs (lncRNAs) play a broad role in GBM, while the role of GSCs subtype remains unknown. Methods: We performed RNA sequencing to explore the lncRNA expression profile in MES- and PN-subtype GBM tissues. The biological function of a host gene-MIR222HG-in GBM development was confirmed in vitro and in vivo. Specifically, RNA sequencing, RNA pulldown, mass spectrometry, RIP, ChIP, luciferase reporter assays and Co-IP were performed. Results: MIR222HG, the expression of which can be induced by SPI1, has high levels in MES GBM tissues. Functionally, we demonstrated that MIR222HG promotes the MES transition and radioresistance in GSCs in vivo and in vitro. Mechanistically, MIR222HG can bind to the YWHAE/HDAC5 complex to promote the MES transition of GSCs through H4 deacetylation. Moreover, cotranscribed miR221 and miR222 can be delivered to macrophages via exosomes to target SOCS3, causing immunosuppressive polarization. Finally, PLX-4720 sensitivity is associated with SPI1 expression and acts on MES GSCs to enhance radiosensitivity. Conclusions: This study demonstrates that targeting SPI1 to block transcription of the MIR222HG cluster helps to reduce radioresistance and combat the immunosuppressive microenvironment in GBM. PLX-4720 is a potential GBM drug and radiosensitizer.
| S-EPMC10283056 | biostudies-literature
Project description:Malic enzyme 2 (ME2) catalyzes the formation of pyruvate from malic acid and is abnormally expressed in some tumors. However, the exact effects of ME2 on proneural-mesenchymal transition (PMT) and lipogenesis in glioblastoma multiforme (GBM) remain unexplored. Here, we found that ME2 expression was significantly higher in GBM than in normal brain tissues and negatively correlated with overall survival of patients with GBM. Furthermore, we demonstrated that ME2 was positively correlated with mesenchymal features in GBM and promoted proliferation, migration, and invasion of glioma cells. Moreover, ME2 upregulated the expression of mesenchymal markers (N-cadherin, vimentin, YKL40, and MET), whereas it inhibited the expression of proneural maker OLIG2, indicating that ME2 might promote PMT in GBM. We also found that ME2 inhibited the production of mitochondrial reactive oxygen species and AMPK phosphorylation, resulting in SREBP-1 maturation and nuclear localization and enhancing the ACSS2 lipogenesis pathway. Taken together, these results suggest that ME2 promotes PMT and is linked with reprogramming of lipogenesis via AMPK-SREBP-1-ACSS2 signaling in GBM. Therefore, ME2 has potential as a new classification marker in GBM and could provide a new approach to glioma treatment.
| S-EPMC8351415 | biostudies-literature