Project description:Glioblastoma multiforme (GBM), a highly malignant and heterogeneous brain tumor, contains various types of tumor and non-tumor cells. Whether GBM cells can trans-differentiate into non-neural cell types, including mural cells or endothelial cells, to support tumor growth and invasion remains controversial. Here we generated two genetic GBM models de novo in immunocompetent mouse brains, mimicking essential pathological and molecular features of human GBMs. Single-cell RNA sequencing showed that patterns of copy-number variations (CNVs) of mural cells and endothelial cells were distinct from those of GBM cells, indicating discrete origins of GBM cells and vascular components. Furthermore, lineage tracing and transplantation studies demonstrated that, although blood vessels in GBM brains underwent drastic remodeling, GBM cells did not give rise to non-neural cell types in the brain. Intriguingly, GBM cells could randomly express mesenchymal markers, including those for mural cells, during gliomagenesis. Most importantly, single-cell CNV analysis of human GBM specimens also strongly suggested that GBM cells and vascular cells are separate lineages. Instead, non-neural cell types expanded by proliferation during tumorigenesis. Therefore, cross-lineage trans-differentiation of GBM cells is very unlikely to occur during gliomagenesis. Our findings advance understanding of cell lineage dynamics during gliomagenesis, and have implications for targeted treatment of GBMs.
Project description:Glioblastoma multiforme (GBM), a highly malignant and heterogeneous brain tumor, contains various types of tumor and non-tumor cells. Whether GBM cells can trans-differentiate into non-neural cell types, including mural cells or endothelial cells, to support tumor growth and invasion remains controversial. Here we generated two genetic GBM models de novo in immunocompetent mouse brains, mimicking essential pathological and molecular features of human GBMs. Single-cell RNA sequencing showed that patterns of copy-number variations (CNVs) of mural cells and endothelial cells were distinct from those of GBM cells, indicating discrete origins of GBM cells and vascular components. Furthermore, lineage tracing and transplantation studies demonstrated that, although blood vessels in GBM brains underwent drastic remodeling, GBM cells did not give rise to non-neural cell types in the brain. Intriguingly, GBM cells could randomly express mesenchymal markers, including those for mural cells, during gliomagenesis. Most importantly, single-cell CNV analysis of human GBM specimens also strongly suggested that GBM cells and vascular cells are separate lineages. Instead, non-neural cell types expanded by proliferation during tumorigenesis. Therefore, cross-lineage trans-differentiation of GBM cells is very unlikely to occur during gliomagenesis. Our findings advance understanding of cell lineage dynamics during gliomagenesis, and have implications for targeted treatment of GBMs.
Project description:Characterization of gene expression for a panel of 50 in vitro and in vivo models of glioblastoma (GBM). Models include subcutaneously established xenograft lines, orthotopically grown subcutaneously established xenograft lines, serum derived cell lines and stem cell media derived cell lines. Multiple replicates of each line were run on different dates to determine the effect of batch and processing date on reproducibility of gene expression profiles 117 samples analyzed from 50 distinct GBM xenografts or cell lines. Biological replicates from the same passage number were included for many, but not all, of the lines.
Project description:Glioblastoma (GBM) is the most common and malignant primary brain tumor. Although immunotherapy has shown promise in certain cancer types, it has not been effective against GBM, largely due to its highly immunosuppressive tumor microenvironment (TMEs), which is rich in tumor-associated macrophages/microglia (TAMs). TAMs in late-stage GBM contribute to T-cell exhaustion and worsen prognosis, but the role of TAMs in earlier stages of tumor development is unclear. By employing genetically engineered mouse models and human samples, we used spatiotemporal single-cell transcriptomics to investigate TAM evolution during GBM progression.
Project description:We investigate whether TAM gene expression is similar between spontaneous and transplanted mouse models of GBM We sort Microglia and monocyte derived macrophages (MDM) from subventricular zone (type 1) and oligodendrocyte progenitor derived (type 2) spontaneous and transplanted mouse GBM tumors and perform bulk RNAseq
Project description:To investigate the transcriotome in glioblastoma tumor and normal brain on a single cell level, we performed RNA sequcening analysis with single cells derived from mouse normal brain tissue or GBM tumor tissue. Particularly, vascular endothelial cells (ECs) were traced using a Cdh5-Cre;LSL-tdTomato system.