Combined MEK and JAK/STAT3 pathway inhibition effectively decreases medulloblastoma tumor progression.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA698708 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13607652.fastq.gz | Fastqsanger.gz | |||
| SRR13607653.fastq.gz | Fastqsanger.gz | |||
| SRR13607654.fastq.gz | Fastqsanger.gz | |||
| SRR13607655.fastq.gz | Fastqsanger.gz | |||
| SRR13607656.fastq.gz | Fastqsanger.gz |
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Project description:RNA sequencing was carried out to identify the signaling pathways and hallmarks that change following MEK and/or JAK/STAT3 pathway inhibition.
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Project description:Medulloblastoma (MB) is the most common primary malignant pediatric brain cancer. We recently identified novel roles for the MEK/MAPK pathway in regulating human Sonic Hedgehog (SHH) MB tumorigenesis. The MEK inhibitor, selumetinib, decreased SHH MB growth while extending survival in mouse models. However, the treated mice ultimately succumbed to disease progression. Here, we perform RNA sequencing on selumetinib-treated orthotopic xenografts to identify molecular pathways that compensate for MEK inhibition specifically in vivo. Notably, the JAK/STAT3 pathway exhibits increased activation in selumetinib-treated tumors. The combination of selumetinib and the JAK/STAT3 pathway inhibitor, pacritinib, further reduces growth in two xenograft models and also enhances survival. Multiplex spatial profiling of proteins in drug-treated xenografts reveals shifted molecular dependencies and compensatory changes following combination drug treatment. Our study warrants further investigation into MEK and JAK/STAT3 inhibition as a novel combinatory therapeutic strategy for SHH MB.
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Project description:Dual inhibition of Src and MEK decreases the growth of human ovarian cancer cells
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Project description:Purpose Integrated genomics approaches have identified at least four distinct biological variants in medulloblastoma: WNT, SHH, group C, and group D. Non-WNT/Non-SHH tumors are associated with metastatic dissemination and an unfavorable prognosis. Additional markers may enhance outcome prediction in Non-WNT/Non-SHH medulloblastomas. Experimental Design We combined transcriptomic and DNA copy-number analyses for 64 primary medulloblastomas. Bioinformatic tools were applied to discover marker genes of molecular variants. Differentially expressed transcripts were evaluated for prognostic value in the screening cohort. Immunopositivity for FSTL5 was correlated with molecular and prognostic subgroups for 235 non-overlapping medulloblastoma samples on two independent tissue microarrays (TMA). Results Unsupervised clustering analyses of transcriptome profiles confirmed four distinct molecular variants. Stable subgroup separation was achieved using only the 300 most varying transcripts. Specific distributions of clinical and molecular characteristics were noted for each cluster. Distinct expression patterns of FSTL5 in each molecular subgroup were confirmed by quantitative real-time PCR. Immunopositivity of FSTL5 identified a large cohort of patients (84 of 235 patients; 36%) at high risk for relapse and death. Importantly, over 50% of Non-WNT/Non-SHH tumors displayed FSTL5 negativity, delineating a large patient cohort with an excellent prognosis who would be considered intermediate/high-risk based on current molecular subtyping. Conclusions Comprehensive analyses of transcriptomic and genetic alterations delineate four distinct variants of medulloblastoma. The addition of FSTL5 immunohistochemistry to existing molecular stratification schemes can effectively identify those Non-WNT/Non-SHH tumors with a poor outcome. Immunohistochemical staining for FSTL5 could be a high-quality and practical tool for stratification and prognostication in future clinical trials of medulloblastoma. Whole-genome transcriptional profiling of human medulloblastomas. Subgrouping based on mRNA expression profiles. Fresh frozen tumor material was collected during tumor resection. Dye-swap design used for expression profiling. Reference was a pool of normal cerebellum tissue from 24 donors. Gene expression profiles illustrate distinct expression pattern at diagnosis. This submission represents the gene expression component of the study.
2011-07-01 | E-GEOD-28245 | biostudies-arrayexpress
Project description:Treatment of established lines and primary ovarian cancer cultures with Src and MEK inhibitors, saracatinib and selumetinib, respectively, showed target kinase inhibition and synergistic induction of apoptosis and cell cycle arrest in vitro and tumor inhibition in xenografts.
2018-03-28 | GSE112371 | GEO
Project description:Isolated neutrophils were exposed to JAK inhibitors then activated with PMA to determine which pathways were dependent on JAK activation
| MSV000099341 | MassIVE
Project description:Purpose Integrated genomics approaches have identified at least four distinct biological variants in medulloblastoma: WNT, SHH, group C, and group D. Non-WNT/Non-SHH tumors are associated with metastatic dissemination and an unfavorable prognosis. Additional markers may enhance outcome prediction in Non-WNT/Non-SHH medulloblastomas. Experimental Design We combined transcriptomic and DNA copy-number analyses for 64 primary medulloblastomas. Bioinformatic tools were applied to discover marker genes of molecular variants. Differentially expressed transcripts were evaluated for prognostic value in the screening cohort. Immunopositivity for FSTL5 was correlated with molecular and prognostic subgroups for 235 non-overlapping medulloblastoma samples on two independent tissue microarrays (TMA). Results Unsupervised clustering analyses of transcriptome profiles confirmed four distinct molecular variants. Stable subgroup separation was achieved using only the 300 most varying transcripts. Specific distributions of clinical and molecular characteristics were noted for each cluster. Distinct expression patterns of FSTL5 in each molecular subgroup were confirmed by quantitative real-time PCR. Immunopositivity of FSTL5 identified a large cohort of patients (84 of 235 patients; 36%) at high risk for relapse and death. Importantly, over 50% of Non-WNT/Non-SHH tumors displayed FSTL5 negativity, delineating a large patient cohort with an excellent prognosis who would be considered intermediate/high-risk based on current molecular subtyping. Conclusions Comprehensive analyses of transcriptomic and genetic alterations delineate four distinct variants of medulloblastoma. The addition of FSTL5 immunohistochemistry to existing molecular stratification schemes can effectively identify those Non-WNT/Non-SHH tumors with a poor outcome. Immunohistochemical staining for FSTL5 could be a high-quality and practical tool for stratification and prognostication in future clinical trials of medulloblastoma.
2011-07-01 | GSE28245 | GEO
Project description:Comparison of Tpl-2 small molecule inhibitor (SMI) versus MEK SMI activities in LPS-treated human monocytes will reveal a subset of genes that require Tpl-2 but are independent of MEK. Tpl-2 is a highly conserved (94% human versus mouse) serine-threonine kinase expressed in cells important to the inflammatory response, including monocytes, macrophages, dendritic cells, and B/T cells. The role of Tpl-2 in monocytes and macrophages has been especially well-studied. It has been shown in these cells that Tpl-2 is required for the expression of cytokines in response to Toll-like receptor ligands, including LPS. In resting cells, Tpl-2 forms a complex with p105 and ABIN-2. Upon stimulation, this complex dissociates. Dissociated p105 is processed to p50, which impacts transcription. Dissociated Tpl-2 phosphorylates MEK, which, in turn, phosphorylates ERK. ERK activates the transcription factor AP-1 and its downstream gene targets. An open question in the field is whether Tpl-2 acts solely through MEK to drive gene expression, or does Tpl-2 have any MEK-independent targets. Answering this question is important both for understanding basic Tpl-2 biology as well as its role in disease. Based on published data, Tpl-2 is important for inflammatory cytokine production, and in animal models where these cytokines contribute to disease (septic shock, IBD), blocking Tpl-2 ameliorates disease symptoms. We have a highly selective SMI of Tpl-2 that effectively blocks cytokine production in purified human monocytes. This SMI can block production of the same cytokines that a MEK inhibitor blocks, which is expected given that Tpl-2 lies upstream of MEK. However, the MEK SMI only partially inhibits certain cytokines, while the Tpl-2 SMI fully blocks them, suggesting there are additional factors downstream of Tpl-2 that are not MEK-dependent.
2019-07-01 | GSE84161 | GEO