RNA-sequencing of the Math1-Cre SmoM2 mouse genetic model of medulloblastoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE104633 | GEO | 2018/01/01
SECONDARY ACCESSION(S): PRJNA413378
REPOSITORIES: GEO
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Project description:Mutations in Hedgehog (Hh) pathway genes, leading to constitutive activation of Smoothened (Smo), occur in sporadic medulloblastoma, the most common brain cancer in children. Antagonists of Smo induce tumor regression in mouse models of medulloblastoma and hold great promise for targeted therapy for this tumor. However, acquired resistance has emerged as one of the major challenges of targeted cancer therapy. Here, we describe novel mechanisms of acquired resistance to Smo antagonists in medulloblastoma. NVP-LDE225, a potent and selective Smo antagonist, inhibits Hh signaling and induces tumor regressions in allograft models of medulloblastoma that are driven by mutations of Patched (Ptch), a tumor suppressor in the Hh pathway. However, after long-term treatment, evidence of acquired resistance was observed. Genome-wide profiling of resistant tumors revealed distinct mechanisms to evade the inhibitory effects of Smo antagonists. Chromosomal amplification of Gli2, a downstream effector of Hh signaling, reactivated Hh signaling and restored tumor growth. Analysis of pathway gene-expression signatures selectively deregulated in resistant tumors identified increased phosphoinosite-3-kinase (PI3K) signaling as another potential resistance mechanism. Probing the functional relevance of increased PI3K signaling, we showed that the combination of NVP-LDE225 with the dual PI3K/mTOR inhibitor NVP-BEZ235 markedly delayed the development of resistance. Our findings have important clinical implications for future treatment strategies in medulloblastoma. mRNA profiling: RNA was prepared from tumours from vehicle or NVP-LDE225 treated nude mice allografted with medulloblastoma tumors derived from Ptch+/-p53-/- transgenic mouse and hybridized on Affymetrix Mouse Genome 430 2.0 RNA expression array. The dosage terminology (BID & QD) reflects the dosing schedule, where BID = twice a day, QD = once a day. aCGH: DNA was prepared from tumors from vehicle or NVP-LDE225 treated nude mice allografted with medulloblastoma tumors derived from Ptch+/-p53-/- transgenic mouse and hybridized on Agilent mouse CGH 244K Array.
2010-09-29 | E-GEOD-19657 | biostudies-arrayexpress
Project description:Mutations in Hedgehog (Hh) pathway genes, leading to constitutive activation of Smoothened (Smo), occur in sporadic medulloblastoma, the most common brain cancer in children. Antagonists of Smo induce tumor regression in mouse models of medulloblastoma and hold great promise for targeted therapy for this tumor. However, acquired resistance has emerged as one of the major challenges of targeted cancer therapy. Here, we describe novel mechanisms of acquired resistance to Smo antagonists in medulloblastoma. NVP-LDE225, a potent and selective Smo antagonist, inhibits Hh signaling and induces tumor regressions in allograft models of medulloblastoma that are driven by mutations of Patched (Ptch), a tumor suppressor in the Hh pathway. However, after long-term treatment, evidence of acquired resistance was observed. Genome-wide profiling of resistant tumors revealed distinct mechanisms to evade the inhibitory effects of Smo antagonists. Chromosomal amplification of Gli2, a downstream effector of Hh signaling, reactivated Hh signaling and restored tumor growth. Analysis of pathway gene-expression signatures selectively deregulated in resistant tumors identified increased phosphoinosite-3-kinase (PI3K) signaling as another potential resistance mechanism. Probing the functional relevance of increased PI3K signaling, we showed that the combination of NVP-LDE225 with the dual PI3K/mTOR inhibitor NVP-BEZ235 markedly delayed the development of resistance. Our findings have important clinical implications for future treatment strategies in medulloblastoma.
2010-09-29 | GSE19657 | GEO
Project description:Aberrant sonic hedeghog signaling is implicated in the development of various cancer entities such as medulloblastoma. The canonical signaling cascade has been studied for years. Activation of GLI transcription factors was revealed as the driving force upon pathway activation. Phosphorylation by Proteinkinase A, Casein Kinase 1 and Glycogen Synthase Kinase 3 β has been found to influence the degradation of the GLI transcription factors. However, the deeper role of phosphorylation in the signal transduction remains unclear. We, therefore, applied comprehensive HPLC-MS/MS based phosphoproteomics to reveal phosphorylation dynamics underlying the chemical activation and inhibition of sonic hedgehog signaling in human medulloblastoma cells. Human medulloblastoma cells were treated with SAG (Hh pathway induction) and Vismodegib (Hh pathway inhibition) for 5 and 15 minutes. Our phosphoproteomic profiling revealed a central role of phosphorylation in the regulation of ciliary assembly, trafficking and signal transduction after 5 minutes treatment. ERK/MAPK signaling besides protein kinase A signaling and mTOR signaling were differentially regulated. Activation of Polo-like kinase 1 and inhibtion of Caseinkinase 2A1 was characteristic for Vismodegib treatment while SAG treatment induced Aurora kinase A activity. Distinctive phosphorylation of central players of sonic Hh signaling such as Smoothened, SUFU, Gli2 and Gli3 was obtained after 15 minutes treatment.
2021-09-08 | PXD013408 | Pride
Project description:Excessive Hedgehog (Hh) signaling activity contributes to fibrosis in multiple organs, however, its role in pancreatic stellate cell (PSC) activation and fibrosis development during chronic pancreatitis (CP) remains unclear. We demonstrate that GLI2 is upregulated in activated PSCs from CP patients and animal models. Specific deletion of Gli2, but not Smo, significantly alleviated fibrosis in CP models, indicating that CP is driven by non-canonical Hh signaling. Experiments on culture-activated primary PSCs reveal early nuclear translocation and increased GLI2 expression promptly after in vitro culture, with GLI2 being essential for PSC activation. SMO inhibition only reduces GLI2 activation in the short term, while activation of GLI2 by TGF-β/SMAD3 signaling explains the SMO-independent mechanisms leading to Hh activation in PSCs. Altogether, our data demonstrate the activation of the non-canonical Hh pathway in PSCs and indicate that GLI2 represents a promising therapeutic target for CP.
2024-11-13 | GSE281427 | GEO
Project description:Aberrations in the Hedgehog (Hh) pathway are known to related to several malignancies. However, little is known about the function of GLI2, a transcription factor in the Hh pathway, in osteosarcoma. Osteosarcoma is the most frequent primary bone sarcoma in children and adolescents. Despite survival rates of osteosarcoma patients have increased, the prognosis of patients with metastasis remains poor. Therefore, the development of novel therapeutic strategies for osteosarcoma patients is development of novel therapeutic strategies for osteosarcoma patients is urgently needed. Aberrations in the Hedgehog (Hh) pathway are known to related to several malignancies. However, little is known about the function of GLI2, a transcription factor in the Hh pathway, in osteosarcoma. Our findings revealed that GLI2 was overexpressed in osteosarcoma tissues. Additionally, GLI2 is involved in the metastasis of osteosarcoma cells through the regulation of ribosomal protein S3 expression. Furthermore, we showed that arsenic trioxide (ATO) suppressed the invasion and lung metastasis of osteosarcoma cells by the inhibition of GLI transcription. Consequently, these finding reveal a novel function of GLI2 in the metastasis of osteosarcoma and that ATO may be a new therapeutic agentay be a new therapeutic agent. We revealed that a novel function of GLI2 in the metastasis of osteosarcoma and that ATO may be a new therapeutic agent for preventing osteosarcoma metastasis. Negative siRNA(U-2OS) and GLI2 siRNA(U-2OS)
2012-12-14 | E-GEOD-42903 | biostudies-arrayexpress
Project description:Despite Hedgehog’s influence on T-cell activation and proliferation, the transcriptional targets of Gli2 in lymphocytes are not known. We therefore examined the Hedgehog-dependent transcriptional response of resting and early-stage activated T-cells in order to define their transcriptional response to Hedgehog pathway activation. We have established transgenic models where transcription of target genes by Gli2 is either constitutively activated or repressed in cells of the T-lineage. Gli2 has an N-terminal repressor domain and a C-terminal activator domain. Lck-Gli2?N2 (Gli2A) mice carry a transgene encoding a truncated form of Gli2 that acts as a permanent transcriptional activator of Hh target genes. Conversely, Lck-Gli2?C2 (Gli2R) mice express a repressor of Gli2-dependent transcription, which by binding to Gli binding sites inhibits physiological Hh-dependent transcription, and hence Hh signal transduction, in the cell. These transgenes are driven by the Lck promoter and are only expressed in T-lineage cells Purified fresh, resting CD4 cells (unstimulated) and from CD4 cells stimulated with anti-CD3/CD28 for 6h (stimulated) were analysed in order to obtain transcriptional profiles before and during the early stages of T-cell activation.
2013-01-01 | E-GEOD-33156 | biostudies-arrayexpress
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:ZNF521 is a transcription co-factor with recognized regulatory functions in haematopoietic, osteo-adipogenic and neural progenitor cells. Among its diverse activities, ZNF521 has been implicated in the regulation of medulloblastoma (MB) cells, where the Hedgehog (HH) pathway, has a key role in the development of normal cerebellum and of a substantial fraction of MBs. Here a functional cross-talk is shown for ZNF521 with the HH pathway, where it interacts with GLI1 and GLI2, the major HH transcriptional effectors and enhances the activity of HH signalling. In particular, ZNF521 cooperates with GLI1 and GLI2 in the transcriptional activation of GLI (glioma-associated transcription factor)-responsive promoters. This synergism is dependent on the presence of the N-terminal, NuRD-binding motif in ZNF521, and is sensitive to HDAC (histone deacetylase) and GLI inhibitors. Taken together, these results highlight the role of ZNF521, and its interaction with the NuRD complex, in determining the HH response at the level of transcription. This may be of particular relevance in HH-driven diseases, especially regarding the MBs belonging to the SHH (sonic HH) subgroup where a high expression of ZNF521 is correlated with that of HH pathway components.
2020-10-03 | GSE158925 | GEO
Project description:Despite Hedgehog’s influence on T-cell activation and proliferation, the transcriptional targets of Gli2 in lymphocytes are not known. We therefore examined the Hedgehog-dependent transcriptional response of resting and early-stage activated T-cells in order to define their transcriptional response to Hedgehog pathway activation. We have established transgenic models where transcription of target genes by Gli2 is either constitutively activated or repressed in cells of the T-lineage. Gli2 has an N-terminal repressor domain and a C-terminal activator domain. Lck-Gli2ΔN2 (Gli2A) mice carry a transgene encoding a truncated form of Gli2 that acts as a permanent transcriptional activator of Hh target genes. Conversely, Lck-Gli2ΔC2 (Gli2R) mice express a repressor of Gli2-dependent transcription, which by binding to Gli binding sites inhibits physiological Hh-dependent transcription, and hence Hh signal transduction, in the cell. These transgenes are driven by the Lck promoter and are only expressed in T-lineage cells
2013-01-01 | GSE33156 | GEO
Project description:Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of many cancers, including medulloblastoma and basal cell carcinoma (BCC). In this study, using neonatally irradiated Ptch1+/- mice as a model of Hh-dependent tumors, we investigated the in vivo effects of MK-4101, a novel SMO antagonist, for treatment of medulloblastoma and BCC. Results clearly demonstrate a robust antitumor activity of MK-4101, achieved through the inhibition of proliferation and induction of extensive apoptosis in tumor cells. Of note, beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1+/- mice. By identifying the changes induced by MK-4101 in gene expression profiles in tumors, we also elucidate the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in the tumor cells, showing the maximum inhibitory effect on Gli1 activity. MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. Members of the IGF and Wnt signaling pathways , were among the most highly deregulated genes by MK-4101, suggesting that the interplay among Hh, IGF and Wnt is crucial in Hh-dependent tumorigenesis. Altogether, the results of this preclinical study support a therapeutic opportunity for MK-4101 in the treatment of Hh-driven cancers, also providing useful information for combination therapy with drugs targeting pathways cooperating with Hh oncogenic activity. Gene expression data was generated (in replicates) from Medulloblastoma allografts collected at various time points and following low (40mpk) or high (80 mpk) or vehicle single dose (QD) or mutiple dose (BID) treatment with a SHH pathway inhibitor.
2016-03-14 | E-GEOD-77042 | biostudies-arrayexpress