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A Protein Neddylation Inhibitor MLN4924 Suppresses Patient-Derived Glioblastoma Cells via Inhibition of ERK and AKT Signaling

ABSTRACT: Glioblastoma is a highly aggressive and lethal brain tumor, with limited treatment options. Abnormal activation of the neddylation pathway is observed in glioblastoma, and the NEDD8-activating enzyme (NAE) inhibitor, MLN4924 was previously shown to be effective in glioblastoma cell line models. However, its effect has not been tested in patient-derived glioblastoma stem cells. Immunohistochemistry and public data were analyzed to determine whether NEDD8 pathway proteins are important in glioblastoma development and patient survival. The effects of MLN4924 were evaluated in 4 glioblastoma cell lines and 15 patient-derived glioblastoma stem cells using high content analysis. Immunoblot analysis assessed the NEDD8 pathway proteins and biomarkers. Whole transcriptome analysis identified pathways associated with MLN4924 sensitivity. NAE1 and UBA3 levels increased in glioblastoma patients; high NEDD8 levels were associated with poor clinical outcomes. Glioblastoma cell lines and patient-derived stem cells were highly susceptible to MLN4924, while normal human astrocytes were resistant. Genomic analyses indicated that MLN4924 sensitive cells exhibited enrichment of ERK and AKT signaling. We verified that MLN4924 inhibits ERK and AKT phosphorylation in MLN4924 sensitive cells. Our findings suggest that patient-derived glioblastoma stem cells in the context of ERK and AKT activation are sensitive and highly regulated by neddylation inhibition.

PROVIDER: EGAS00001004018 | EGA |

REPOSITORIES: EGA

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Project description:A Protein Neddylation Inhibitor MLN4924 Suppresses Patient-Derived Glioblastoma Cells via Inhibition of ERK and AKT Signaling

| PRJEB35293 | ENA

PI3K/AKT signaling allows for MAPK/ERK pathway independency mediating dedifferentiation-driven treatment resistance in melanoma

Project description:Current therapeutic management of advanced melanoma patients largely depends on their BRAF mutation status. However, the vast heterogeneity of the tumors hampers the success of therapies targeting the MAPK/ERK pathway alone. Dissecting this heterogeneity will contribute to identifying key players in the oncogenic progression to tailor more effective therapies. We performed a comprehensive molecular and phenotypic characterization of a panel of patient-derived BRAFV600E-positive melanoma cell lines. Transcriptional profiling was used to identify groups of coregulated genes whose expression relates to an increased migratory potential and a higher resistance. A decrease in sensitivity to MAPK/ERK pathway inhibition with vemurafenib or trametinib corresponded with an increasing quiescence and migratory properties of the cells. This was accompanied by the loss of transcriptional signatures of melanocytic differentiation, and the gain of stem cell features that conferred highly-resistant/mesenchymal-like cells with increased xenobiotic efflux capacity. Nevertheless, targeting of the implicated ABC transporters did not improve the response to vemurafenib, indicating that incomplete BRAF inhibition due to reduced drug uptake is not a main driver of resistance. Rather, indifference to MAPK/ERK pathway inhibition arose from the activation of compensatory signaling cascades. The PI3K/AKT pathway in particular showed a higher activity in mesenchymal-like cells, conferring a lower dependency on MAPK/ERK signaling and supporting stem-like properties that could be reverted by dual PI3K/mTOR inhibition with dactolisib. In case of MAPK/ERK independency, therapeutic focus may be shifted to the PI3K/AKT pathway to overcome late-stage resistance in melanoma tumors that have acquired a mesenchymal phenotype.

2022-09-01 | GSE208004 | GEO

Metabolic heterogeneity in Glioblastoma

Project description:2 cell populations [slow and fast-cycling cells] were isolated from 3 different patient-derived glioblastoma stem cell lines [L0, L1, L2].

2015-03-24 | ST000248 | MetabolomicsWorkbench

Myeloid-derived suppressor cells promote lung cancer metastasis

Project description:Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune activities and facilitate cancer progression. Although the concept of immunosuppressive MDSCs is well established, the mechanism that MDSCs regulate non-small cell lung cancer (NSCLC) progression through the paracrine signals is still lacking. Here, we reported that the infiltration of MDSCs within NSCLC tissues were associated with the progression of cancer status, and were positively correlated with the Patient-derived xenograft (PDX) model establishment, and poor patient prognosis. Intratumoral MDSCs directly promoted NSCLC metastasis and highly expressed chemokines that promote NSCLC cells invasion, including CCL11. CCL11 was capable of activating the AKT and ERK signaling pathways to promote NSCLC metastasis through the epithelial-mesenchymal transition (EMT) process. Moreover, high expression of CCL11 was associated with a poor prognosis in lung cancer as well as other types of cancer. Our findings underscore that MDSCs produce CCL11 to promote NSCLC metastasis via activation of ERK and AKT signaling and induction of EMT, suggesting that the MDSCs-CCL11-ERK/AKT-EMT axis contains potential targets for NSCLC metastasis treatment.

2021-01-17 | GSE136949 | GEO

Patient-derived glioblastoma stem cells transcriptome regulation by CD109

Project description:Patient-derived glioblastoma stem cells transcriptome regulation by CD109

| PRJNA716553 | ENA

A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma [Illumina]

Project description:Abstract. Background: Glioblastoma is the most common primary malignancy of the central nervous system with dismal prognosis. Differential gene expression classifies IDH-wildtype glioblastoma into three subtypes: proneural, mesenchymal and classical. Dasatinib, an inhibitor of the proto-oncogene tyrosine-protein kinase SRC, is one of many therapeutics that, despite promising preclinical results, has failed to improve overall survival in glioblastoma patients in clinical trials. We examined whether glioblastoma subtypes differ in their response to dasatinib therapy and could hence be used for patient enrichment strategies in clinical trials. Methods: We carried out in silico analyses of the TCGA glioblastoma gene expression data and single-cell RNA-Seq data, in combination with in vitro experiments using glioblastoma stem-like cells (GSCs) derived from primary patient tumors with complimentary gene expression profiling and immunohistochemistry analyses of tumor samples. Results: Patients suffering from the mesenchymal subtype of glioblastoma showed higher SRC pathway activation based on gene expression profiling, and accordingly, mesenchymal cells were more sensitive to SRC inhibition by dasatinib compared to proneural and classical cells. Furthermore, SERPINH1, a heat-shock protein relevant in many cancer entities, was shown to highly correlate with dasatinib response and with the mesenchymal subtype. Notably, SRC phosphorylation status was not able to reliably predict response to dasatinib treatment. Conclusion: This work highlights the need for rational methods of patient selection for clinical trials, and retrospectively sheds light on a possible gene expression subtype-led patient stratification strategy that could have improved the outcome of SRC inhibition in patients and could have implications for future trials.

2020-10-20 | GSE159607 | GEO

A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma [Agilent]

2020-10-20 | GSE159605 | GEO

Adherent and Spheroid Glioblastoma Proteomics

Project description:Dendritic cell (DC)-based immunotherapy against glioblastoma multiforme is a novel treatment hope. Glioblastoma stem-like cells are, however, potentially causing immunoresistance. Glioblastoma cells cultured as gliomaspheres show a stem-like phenotype as opposed to classical adherent culture. They are thus a promising antigen source to specifically target glioblastoma stem-like cells via DC therapy and so overcome immunoresistance. Here we study the importance of gliomasphere-specific. Methodologically, we used 7 gliomaspheres, 3 of them patient-derived, as model system. Gliomasphere-specific protein expression was explored via quantitative proteomics.

2019-04-15 | PXD008244 | Pride

Human PUS7 in tRNA pseudouridylation

Project description:Pseudouridine is the first discovered and the most frequent modification in RNA. However, its biological functions in physiology and human diseases are largely unknown. Here, we show that pseudouridine synthase PUS7 is differentially expressed in glioblastoma patient tissues verse non-tumor brain tissues, and highly expressed in patient brain-derived cancer stem cells, compared to normal brain-derived neural stem cells. Upregulated expression of PUS7 predicts worse survival in glioblastoma patients in multiple databases. Indeed, we show that PUS7 plays an important role in regulating the self-renewal and tumorigenesis of glioblastoma stem cells. Overexpression of the wild type but not the catalytically inactive PUS7 increases the growth and self-renewal of GSCs. In contrast, knockdown of PUS7 dramatically suppresses GSC growth, self-renewal and tumorigenesis. Mechanistically, knockdown of PUS7 activates interferon pathway through translational control of TYK2 via PUS7-regulated tRNAs. Moreover, we have identified chemical inhibitors for PUS7 in this study. These chemical compounds target pseudouridine modification and suppress GSC growth and tumorigenesis, providing a potential therapeutic tool for GBM treatment.

2021-06-18 | GSE147342 | GEO

Gene expression profiling of patient-derived glioblastoma stem cell cultures

Project description:To identify proneural, neural, classical and mesenchymal gene expression signature (Verhaak's classification) in human glioblastoma, a microarray analysis on 16 patient-derived glioblastoma stem cell cultures was performed.

2018-06-26 | E-MTAB-6408 | biostudies-arrayexpress

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