Thrombospondin-1 in glioblastoma development
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ABSTRACT:
PROVIDER: PRJEB23786 | ENA |
REPOSITORIES: ENA
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Project description:Gliomas synaptically integrate into neural circuits. Prior work has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth and gliomas increasing neuronal excitability. In this study we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumor tissue biopsies and cell biology experiments, we found that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumor-infiltrated cortex well beyond the cortical regions normally recruited in the healthy brain. Site-directed biopsies from regions within the tumor that exhibit high functional connectivity between the tumor and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumor cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumor regions compared to tumor regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 through the FDA-approved drug, gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively impacts both patient survival and language task performance. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumor progression and impairs cognition.
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Project description:Thrombospondin 1 (TSP-1) is an anti-angiogenic matricellular protein with regulatory functions in inflammation and cancer. The type 1 repeats (TSR) domains of TSP-1 have been shown to interact with a wide range of proteins that result in the anti-angiogenic and anti-tumor properties of TSP-1. To evaluate potential therapeutic effects of TSRs in inflammatory bowel disease, we conducted clinical, histological and gene microarray analyses on a mouse model of induced colitis. We used Affymetrix GeneChips to determine the changes in the genetic profile underlying TSR-treatment coincident with induction of colitis using DSS. We identified differentially expressed genes among the treatment groups.
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Project description:Here, we analyzed patient-derived glioblastoma xenografts generated in the mouse brain that give rise to three different histological phenotypes: (i) a highly invasive phenotype (ii) a highly angiogenic phenotype and (iii) an intermediate phenotype. Cell type-specific transcriptomic profiles of tumor and stromal endothelial cells were analyzed to reveal phenotype-specific gene expression patterns and the reciprocal crosstalk between tumor and stromal endothelial cells. This part of the study contains the analysis of the stromal endothelial cells of the host mice. The analysis of the patient-derived tumor cells is found under E-MTAB-3948.
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Project description:Here, we analyzed patient-derived glioblastoma xenografts generated in the mouse brain that give rise to three different histological phenotypes: (i) a highly invasive phenotype (ii) a highly angiogenic phenotype and (iii) an intermediate phenotype. Cell type-specific transcriptomic profiles of tumor and stromal endothelial cells were analyzed to reveal phenotype-specific gene expression patterns and the reciprocal crosstalk between tumor and stromal endothelial cells. This part of the study contains the analysis of the patient-derived tumor cells. The analysis of the stromal endothelial cells of the host mice is found under E-MTAB-3949.
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Project description:Thrombospondin 1 (TSP-1) is an anti-angiogenic matricellular protein with regulatory functions in inflammation and cancer. The type 1 repeats (TSR) domains of TSP-1 have been shown to interact with a wide range of proteins that result in the anti-angiogenic and anti-tumor properties of TSP-1. To evaluate potential therapeutic effects of TSRs in inflammatory bowel disease, we conducted clinical, histological and gene microarray analyses on a mouse model of induced colitis. We used Affymetrix GeneChips to determine the changes in the genetic profile underlying TSR-treatment coincident with induction of colitis using DSS. We identified differentially expressed genes among the treatment groups. Using DSS (dextran sulfate sodium) to induce colitis, wild-type mice were simultaneously injected with either saline or one form of TSP-1 derived peptides, containing either the three domains of the TSR (3TSR), the two last domains (TSR2), or TSR2 with the RFK sequence (TSR2+RFK). Wt mice drinking water only was used as reference.
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Project description:Glioblastoma tumour cells release microvesicles (exosomes) containing mRNA, miRNA and angiogenic proteins. These microvesicles are taken up by normal host cells, such as brain microvascular endothelial cells. By incorporating an mRNA for a reporter protein into these microvesicles, we demonstrate that messages delivered by microvesicles are translated by recipient cells. These microvesicles are also enriched in angiogenic proteins and stimulate tubule formation by endothelial cells. Tumour-derived microvesicles therefore serve as a means of delivering genetic information and proteins to recipient cells in the tumour environment. Glioblastoma microvesicles also stimulated proliferation of a human glioma cell line, indicating a self-promoting aspect. Messenger RNA mutant/variants and miRNAs characteristic of gliomas could be detected in serum microvesicles of glioblastoma patients. The tumour-specific EGFRvIII was detected in serum microvesicles from 7 out of 25 glioblastoma patients. Thus, tumour-derived microvesicles may provide diagnostic information and aid in therapeutic decisions for cancer patients through a blood test.
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Project description:Glioblastoma cells are characterized by a highly invasive behavior whose mechanisms are not yet understood. Using the wound healing and Boyden chamber assays we compared in the present study the migration and invasion abilities of 5 glioblastoma cell lines (DK-MG, GaMG, U87-MG, U373-MG, SNB19) differing in p53 and PTEN status. We also analyzed by Western blotting the expression of PTEN, p53, mTOR and several other marker proteins involved in cell adhesion, migration and invasion. Among 5 cell lines, GaMG cells exhibited the fastest rate of wound closure, whereas U87-MG cells showed the most rapid chemotactic migration in the Boyden chamber assay. In DK-MG and GaMG cells, F-actin mainly occurred in the numerous stress fibers spanning the cytoplasm, whereas U87-MG, U373-MG and SNB19 cells preferentially expressed F-actin in filopodia and lamellipodia. Moreover, the two glioblastoma lines mutated in both p53 and PTEN genes (U373-MG and SNB19) were found to exhibit the fastest invasion rates through the Matrigel matrix. Here, we performed a gene expression profiling of the five glioblastoma cell lines to examine the molecular framework of differences in invasive behavior to find possible targets for chemo- and radiation therapy.
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Project description:Malignant glioblastoma (GBM) is a highly aggressive brain tumor with a dismal prognosis and limited therapeutic options. Genomic profiling of GBM samples in the TCGA database has identified four molecular subtypes (Proneural, Neural, Classical and Mesenchymal), which may arise from different glioblastoma stem-like cell (GSC) populations. In the present study, we identify two GSC populations that produce GBM tumors by subcutaneous and intracranial injection with identical histological features. Gene expression analysis revealed that xenografts of GSCs grown as spheroid cultures had a Classical molecular subtype similar to that of bulk tumor cells. In contrast xenografts of GSCs grown as adherent cultures on laminin-coated plates expressed a Mesenchymal gene signature. Adherent GSC-derived xenografts had high STAT3 and ANGPTL4 expression as well as enrichment for stem cell markers, transcriptional networks and pro-angiogenic markers characteristic of the Mesenchymal subtype. Examination of clinical samples from GBM patients showed that STAT3 expression was directly correlated with ANGPTL4 expression, and that increased expression of these genes correlated with poor patient survival and performance. A pharmacological STAT3 inhibitor abrogated STAT3 binding to the ANGPTL4 promoter and exhibited anticancer activity in vivo. Taken together, we identified two distinct GSC populations that produce histologically identical tumors but with very different gene expression patterns, and a STAT3/ ANGPTL4 pathway in glioblastoma that may serve as a target for therapeutic intervention. 2 samples of each variable were analyzed. Cells were cultured under normal adherent conditon (Bulk tumor cells), non-adherent plates with stem cell medium (Sp-GSC) or laminin-coated plates with stem cell medium (Ad-GSC). Xenografts were generated in NSG mice by subcutaneous inoculation.
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