Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA190094 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Mice bearing primary human chondrosarcoma xenografts were treated with IPI 926, and mRNA levels of known Hh pathway genes and endpoint tumor volumes were measured. Gene expression profiling of IPI-926 treated tumors was conducted to identify potential novel Hh target genes. 4 Control treated and 4 IPI-926 treated NSG Mice. Primary tumor was obtained from a single chondrosarcoma patient.
2014-03-18 | E-GEOD-44581 | biostudies-arrayexpress
Project description:Mice bearing primary human chondrosarcoma xenografts were treated with IPI 926, and mRNA levels of known Hh pathway genes and endpoint tumor volumes were measured. Gene expression profiling of IPI-926 treated tumors was conducted to identify potential novel Hh target genes.
2014-03-18 | GSE44581 | GEO
Project description:Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model
| PRJNA160117 | ENA
Project description:Aberrant hedgehog (Hh) signaling contributes to the pathogenesis of multiple cancers. Currently available inhibitors target Smoothened, which can acquire mutations causing drug resistance. Thus, compounds that inhibit Hh signaling downstream of Smoothened are urgently needed. We identified dynarrestin, a novel inhibitor of cytoplasmic dyneins 1 and 2 by using achemical proteomics approach. Dynarrestin acts reversibly to inhibit cytoplasmic dynein 1-dependent microtubule binding and motility in vitro without affecting ATP hydrolysis. It rapidly and reversibly inhibits endosome movement in living cells and perturbs mitosis by inducing spindle misorientation and a pseudoprometaphase delay. Dynarrestin reversibly inhibits intraflagellar transport (IFT) of the cargo IFT88 and flux of Smoothened within cilia without interfering with ciliogenesis as well as suppresses Hh-dependent proliferation of neuronal precursors and tumor cells. As such, dynarrestin is a valuable new tool for probing cytoplasmic dynein-dependent cellular processes and a promising lead compound for medicinal chemistry programs aimed at development of anti-cancer drugs.
2018-08-08 | PXD004440 | Pride
Project description:We report a novel resistance mechanism to CDK4/6 inhibition in Hedgehog-associated medulloblastoma where cell models and mouse models demonstrate that prolonged inhibition of CDK4/6 inhibits ribosome biogenesis, activates the unfolded protein response, and increases the amount of Smoothened-activating lipids. This RNA-Sequencing dataset represents genomically-engineered mouse medulloblastoma models that either have wild-type Cdk6 or genomic knockout of Cdk6. We find that tumors that grew despite genetic loss of Cdk6 have suppresed ribosome biogenesis.
2021-01-06 | GSE164311 | GEO
Project description:Resistance to clinically available targeted drugs has become a critical issue in hedgehog-driven cancer treatment. Our previous studies have demonstrated two epigenetic/transcriptional targeted therapeutic strategies, BET inhibition and CDK7 inhibition, could overcome both primary and acquired resistance to Smoothened inhibitor (SMOi) drugs, providing a promising direction for novel anti-hedgehog drug development. In this study, we performed CRISPR-Cas9 screening of epigenetic/transcriptional targeted sgRNA library in hedgehog-driven medulloblastoma (SHH-MB) cells and combined with tumor dataset analyses to identify other potential epigenetic/transcriptional targeted strategies for treating aberrant hedgehog pathway and overcoming SMOi-resistance. Our results demonstrated structure specific recognition protein 1 (SSRP1), a subunit of Facilitates Chromatin Transcription (FACT) complex, was a hedgehog-induced essential oncogene and therapeutic target of hedgehog-driven cancer. FACT inhibitor CBL0137, which has entered human clinical trials against cancer, could effectively suppress multiple mouse and human hedgehog-driven cancer models that are either SMOi-responsive or -resistant both in vitro and in vivo. Mechanistically, CBL0137 exerted its anti-hedgehog activity mainly through targeting the transcription of GLI1/2, which are core transcription factors of hedgehog pathway. ChIP-qPCR analyses further revealed SSRP1 could bind to the promoter regions of GLI1/2, while CBL0137 treatment substantially disrupted these interactions. Moreover, CBL0137 could work synergistically with BET inhibitor or CDK7 inhibitor on antagonizing aberrant hedgehog pathway and growth of either SMOi-responsive or -resistant hedgehog-driven cancer models. Taken together, our study identified FACT inhibition as another promising epigenetic/transcriptional targeted therapeutic strategy for treating hedgehog-driven cancer and overcoming SMOi-resistance.
2021-07-08 | GSE171685 | GEO
Project description:We determined the immune cell composition and their gene expression, by performing single-cell RNA sequencing (scRNA-seq), in anti-PD-L1-treated 2F8cis tumors, a hot and immunoresponsive ovarian murine tumor model, and anti-PD-L1-treated 2F8cis/CA-MSC tumors. We also evaluated the ability of hedgehog inhibitor (HHi) therapy to reverse CA-MSC effects. Adipose-derived mesenchymal stem cells (MSC) were cultured with 2F8cis, an ovarian mouse tumor cell line, to generate cancer-associated MSC (CA-MSC). 2F8cis tumor cell alone or 2F8cis/CA-MSCs co-cultured cells at ratio 1:1 were injected into C57BL/6J mice. Tumor infiltrating CD45+ cells were isolated from anti-PD-L1-treated 2F8cis (Group 1, n=3), anti-PD-L1-treated 2F8cis/CA-MSCs (Group 2, n=3), anti-PD-L1+ IPI-926-treated 2F8cis/CA-MSCs (Group 3, n=3) tumors. Samples were labeled with different TotalSeq oligo-conjugated antibodies and loaded into the Chromium instrument (10x Genomics). The resulting barcoded cDNAs were used to construct libraries. Single-cell cDNA libraries were then processed for RNA sequencing using an Illumina NextSeq-500 platform. Anti-PD-L1-treated 2F8cis/CA-MSC tumors showed a high number of Monocytes and macrophages over-expressing Ccr2 and Tgfbi when compared to anti-PD-L1 responsive 2F8cis tumors. Our results also indicated that IPI-926 restored response to anti-PD-L1 therapy decresing the expression of Ccr2 and Tgfbi both in monocytes and macrophages. Our study represents the first detailed analysis generated by RNA-seq technology of 2F8cis/CA-MSC+ enriched tumor transcriptomes, treated with anti-PDL1 alone or in combination with HHi, and compared with anti-PDL1-treated tumors. The optimized data analysis workflows reported here should provide a framework for comparative investigations of expression profiles.
2021-10-06 | GSE185013 | GEO
Project description:Targeting Hedgehog pathway by Smoothened Antagonist
| PRJNA720577 | ENA
Project description:The Hedgehog (Hh) pathway is essential for tissue homeostasis, and misregulation of this cascade drives several cancers. To control expression of pathway target genes, the G protein-coupled receptor (GPCR) Smoothened (SMO) activates glioma-associated (GLI) transcription factors via an unknown mechanism. Here we show that, rather than conforming to traditional GPCR signaling paradigms, SMO activates GLI by binding and sequestering protein kinase A (PKA) catalytic subunits at the membrane. This sequestration, triggered by GPCR kinase 2 (GRK2)-mediated phosphorylation of SMO intracellular domains, prevents PKA from phosphorylating soluble substrates, releasing GLI from PKA-mediated inhibition. Our work provides a mechanism directly linking vertebrate Hh signal transduction at the membrane to transcription factor activation in the nucleus. In contrast to existing models, our work shows that this aspect of Hh signaling is fundamentally similar between species. The mechanism described here may apply broadly to other GPCR- and PKA-containing cascades.
2021-04-25 | PXD019346 | Pride
Project description:RNA sequencing is used to compare genes regulated by a constitutively active form of Smoothened, a protein critical to Hedgehog signaling, and a constitutively active form of the alpha subunit of the heterotrimeric G proteins G13, which shares some of the primary actions of Smoothened.
2018-05-05 | GSE98841 | GEO