Project description:Glioblastoma is the deadliest adult brain cancer and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 months over surgery alone but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype and identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP caused loss of radiation-induced Nanog mRNA expression, activation of GSK3 with consecutive post-translational reduction in p-Akt, Sox2 and -catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of glioblastoma. Our findings suggest that combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in glioblastoma by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment resistant, induced GICs.
Project description:GICs are considered a major determinant in glioblastoma treatment failure, as they exhibit a marked resistance to radiotherapy. However, the exact mechanisms that confer this radioresistance to GICs are still not fully understood. We have performed a microarray analysis after radiation treatment of GICs and non-GICs cultures with the aim of identifying genes, pathways and transcription factors differentially expressed between these two cellular compartments.
Project description:Purpose: Organisms constantly face environmental stressors that threaten their cellular and genomic integrity. In their response, pathogen-associated molecular patterns (PAMPs) and/or damage-associated molecular patterns (DAMPs) are detected by pattern recognition receptors (PRRs) and trigger the innate immune response. In this study we tested the hypothesis that DAMPs contribute to radiation-induced cellular plasticity in Glioblastoma (GBM). GBM is known to be organized hierarchically with a small number of glioma-initiating cells (GICs) driving treatment resistance and recurrences. Materials and Methods: Using patient-derived GBM specimens, we employed sphere forming capacity assays and in vitro extreme limiting dilution assays to examine how innate immune receptor signaling impacts the maintenance and self-renewal of GICs. By leveraging an imaging system for putative GICs we determined de novo induction of GICs from non-stem glioma cells. Results: We find that GIC maintenance after irradiation is mediated by cGAS-independent STING signaling, possibly involving signaling through TLR4 and TLR9. Induction of radiation-induced plasticity involves TLR3 signaling, with potential roles for other receptors and processes modulated by MyD88. Conclusion: These findings suggest that targeting innate immune signaling could prevent radiation-induced cellular plasticity for potential therapeutic benefit.
Project description:A mesenchymal transition occurs both during natural evolution of glioblastoma (GBM) and in response to therapy. However, the molecular mechanisms underlying mesenchymal differentiation are not well understood. We have found that the adhesion G protein-coupled receptor GPR56/ADGRG1 inhibits mesenchymal differentiation and radioresistance in glioblastoma stem-like initiating cells (GICs). Here, we have performed microarray analysis of parental- versus GPR56 knockout-GICs to identify gene expression changes upon GPR56 knockout
Project description:We evaluated the gene expression profiles of the 1228- and 0316-Glioma-initiating cells (GICs), as well as the original glioblastoma tissues from which they were derived, plus neural stem cells and normal brain tissues. Short- and long-term cultures of 0316-GICs (2 and 6 months, respectively) were also included in the analysis in order to evaluate the potential effects of in vitro culture duration on gene expression. Expressional changes by EZH2 depletion and DZnep treatment were also evaluated.
Project description:A mesenchymal transition occurs both during natural evolution of glioblastoma (GBM) and in response to therapy. However, the molecular mechanisms underlying mesenchymal differentiation are not well understood. We have found that the adhesion G protein-coupled receptor, GPR56/ADGRG1, inhibits mesenchymal differentiation and radioresistance in glioblastoma stem-like initiating cells (GICs). Here, we have performed microarray analysis of control- versus GPR56 knockdown-GICs to characterize gene expression changes upon GPR56 knockdown and identify a gene expression signature associated to GPR56.
Project description:To identify a novel miRNA that is aberrantly expressed in GICs, we analyzed differences in miRNA expression between the mouse GICs, NSCL61 and OPCL61, showing characteristic features of cancer stem cell, and their parental cells by miRNA microarrays. neural stem cells, glioma-initiating cells (GICs) from neural stem cells, oligodendrocyte precursor cells, glioma-initiating cells (GICs) from oligodendrocyte precursor cells.
Project description:The invasive nature of glioblastoma (GBM) represents a major clinical challenge contributing to poor outcomes. Invasion of GBM into healthy tissue restricts therapeutic access and surgical resection. Therefore, effective anti-invasive strategies of GBM cells can be key to increase the efficacy of chemotherapy against this devastating disease. As cancer stem or initiating cells are considered to retain the tumorigenic potential in a number of tumors including glioblastoma, we studied the invasion capabilities of glioblastoma initiating cells (GICs) that were isolated from the peritumoral (PT) tissue, which surrounds the tumor mass (TM) and remains in the brain after tumor removal. We found that PT-GICs are less proliferative but more invasive compared to TM-GICs. Gene expression arrays of cells derived from the tumor mass and the peritumoral tissue of three glioblastoma cases
