Project description:To understand the diversity of expression states within human gliomas, we obtained eleven freshly resected glioma-related samples, profiled ~3000 cells from each sample and examined their diversity.
Project description:Six freshly resected recurrent glioma samples were obatined to analyze the diversity of expression states of human gliomas. About 3000 cells from each sample were profiled.
Project description:This work lays the foundation for the intratumoral immune infiltrates of glioma patients analyzed at a single cell level with the dual purpose of establishing the relevance of a new mouse model of GBM with regard to the patient disease. The aim of this study was to determine the level of concordance between the spontaneous and implanted Qk/trp53/Pten (QPP) triple-knockout mouse GBM model and human glioma samples in regard to their immune infiltrates.We analyzed a cohort of fifteen spontaneous QPP mice, nine implanted QPP mice and 10 glioma patients histopathologically. Furthermore, we analyzed three spontaneous QPP mice, thee implanted QPP mice, and 10 glioma patients by single cell RNA sequencing. We found that the QPP model recapitulates human GBM regarding the major immune components including a predominantly myeloid cell population of monocytes, macrophages, and resting dendritic cells, with minor populations of T, B, and NK cells. In addition, the complexity of the myeloid cell populations is preserved between the QPP model and the human disease.
Project description:Recent single-cell transcriptomic studies report that IDH-mutant gliomas share a common hierarchy of cellular phenotypes, independent of genetic subtype. However, the genetic differences between IDH-mutant glioma subtypes are prognostic, predictive of response to chemotherapy, and correlate with distinct tumor microenvironments. To reconcile these findings, we profiled 22 human IDH-mutant gliomas via single-cell assay for transposase-accessible chromatin (scATAC-seq). We determined the cell-type specific differences in transcription-factor expression and associated regulatory grammars between IDH-mutant glioma subtypes. We find that while IDH-mutant gliomas do share a common distribution of cell types, there are significant differences in the expression and targeting of transcription factors that regulate glial identity and cytokine elaboration. We knocked out the chromatin-remodeler ATRX, which suffers loss-of-function alterations in most IDH-mutant astrocytomas, in an IDH-mutant immunocompetent intracranial murine model. We find that both human ATRX-mutant gliomas and murine ATRX-knockout gliomas are more heavily infiltrated by immunosuppressive monocytic-lineage cells derived from circulation than ATRX-intact gliomas, in an IDH-mutant background. ATRX knockout in murine glioma recapitulates gene expression and open-chromatin signatures that are specific to human ATRX-mutant astrocytomas, including drivers of astrocytic lineage and immune-cell chemotaxis. ATRX knockout in murine glioma recapitulates gene expression and open chromatin signatures that are specific to human ATRX-mutant astrocytomas, including drivers of astrocytic lineage and immune-cell chemotaxis. Through single-cell cleavage under targets and tagmentation assays and meta-analysis of public data, we show that ATRX loss leads to a global depletion in CCCTC-binding factor association with DNA, gene dysregulation along associated chromatin loops, and protection from therapy-induced senescence.