GAS7 Deficiency Promotes Metastasis of MYCN-driven Neuroblastoma
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE131307 | GEO | 2021/02/04
REPOSITORIES: GEO
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Project description:High levels of LMO1 expression synergizes with MYCN to accelerate neuroblastomagenesis, enhance disease penetrance and promote widespread metastasis in zebrafish. Transcriptomic analysis of human neuroblasotma cells with programed expression of LMO1 vs vector control or neuroblastoma cells with differential endogenous LMO1 expression revealed that gene signitures affecting tumor cell-extracellular matrix interaction are significantly associated with high levels of LMO1 expression. Our findings provide compelling evidence for a major pathogenic role of LMO1 in MYCN-driven neuroblastoma.
2017-07-31 | GSE90087 | GEO
Project description:Neuroblastoma (NB) with MYCN amplification is a highly metastatic tumor in children, and unraveling the key players involved in MYCN-induced invasion may identify new targets for therapy. Epithelial-mesenchymal transition (EMT) plays a critical role in promoting metastasis and we have recently determined that MYCN interacts with LSD1, a histone de-methylase flavin oxidase, which has been found to promote EMT. We show here that LSD1 affects motility and invasiveness of NB cells through transcription modulation of the metastasis suppressor NDRG1, N-Myc Downstream-Regulated Gene 1. LSD1 co-localizes with MYCN at the promoter region of the NDRG1 gene and it inhibits its expression. LSD1-inhibition relieves NDRG1 repression induced by MYCN with concomitant block of motility and invasiveness of NB cells, and such effects were recapitulated by overexpressing NDRG1. Moreover, we found that low NRDG1 and high LSD1 levels in NB patients were associated with poor survival. These data suggest that LSD1 inhibition may knock down the ability of MYCN-amplified Neuroblastomas to metastasize. Our findings elucidate a mechanism of how MYCN/LSD1 control motility and invasiveness of NB cells through transcription regulation of NDRG1 expression and they suggest that pharmacological targeting of LSD1 could inhibit the NB metastatic process.
2016-12-31 | GSE80753 | GEO
Project description:Neuroblastoma (NB) is an embryonic tumor arising from immature sympathetic nervous system progenitor cells. MYCN and ALK are driver oncogenes both of which are specifically expressed during early neurogenesis. This is in line with the assumption that NB arises through disruption of normal developmental processes. MYCN has a broad impact on the tumor phenotype; however, the details of the MYCN driven oncogenic program are far from clear. In recent studies we demonstrated that MYCN drives the expression of a defined set of miRNAs that tightly control the expression of several key MYCN target genes, including several components of the TGFβ signaling pathway. In order to gain further insight into the role of miRNAs in NB initiation and progression, we evaluated miRNA profiles of hyperplastic ganglia and tumors isolated from MYCN transgenic mice.
2014-10-01 | E-MTAB-2618 | biostudies-arrayexpress
Project description:Neuroblastoma (NB) is an embryonal tumor with various clinical presentations and behaviors. Several genomic alterations has been well-studied in NB, among which genomic amplification of MYCN oncogene, is a strong prognostic biomarker with worsens outcome. Long noncoding RNAs (lncRNAs), constitute major proportion of the cellular transcripts with no coding capacity. One of their function is to guide transcription factors to the target genes and facilitate gene expression. However, relative contribution of lncRNA and MYCN to the advanced NB has remained unclear. Herein, by applying a network-based integrative analysis on MYCN amplified and MYCN nonamplified lncRNA expression profile from both RNA-seq and microarray platform, we identified lncRNA, SNHG1 to be differentially expressed and strongly correlated with MYCN in MYCN-amplified NB. The expression of SNHG1 was validated by RT-qPCR in NB cell lines. Survival analysis revealed that higher expression of SNHG1 significantly associates with poor patient survival. Moreover, knockdown of MYCN in MYCN-amplified NB cell lines inhibited SNHG1 expression. Furthermore, to unravel the role of SNHG1 in NB, we extracted SNHG1-interacting proteins by RNA-protein pull down assay coupled with doi:10.6342/NTU201701980 ! ! VI liquid chromatography-tandem mass spectrometry (LC-MS/MS). We identified 27 SNHG1-interacting proteins in common from three NB cell lines. However, only three SNHG1-interacting proteins, MATR3, YBX1 and HHRNPL have binding site detected by DeepBind motif analysis. Western blot confirms interaction of MATR3 with SNHG1. Additionally, we further validated the direct interaction between MATR3 and SNHG1 by RNA-immunoprecipation (IP). MATR3 is known to be involved in RNA transport and stabilization. Therefore, we proposed that MATR3 after interacting with SNHG1 might help in SNHG1 transcription and stabilization. In conclusion, our study unveils that SNHG1 could be a prognostic marker for high-risk NB and possibly stabilized by MATR3. Our results might provide future directions for the development of therapeutic strategies against high-risk NB.
2022-03-01 | PXD007121 | Pride
Project description:Tumors were divided into two biologically based groups by the following criteriaï¾s: Favorable (F); NB patient with no evidence of disease (NED) with a primary tumor staged 1-3 with no MYCN-amplification, no 1pdel, and no 11qdel. Unfavorable (UF); NB patient with advanced stage of disease or dead of disease (DOD) with a primary tumor staged 4, or with a primary tumor staged 3 with MYCN-amplification and/or 1pdel and/or 11qdel
2009-09-05 | E-MEXP-2250 | biostudies-arrayexpress
Project description:Neuroblastoma (NB) is a paediatric tumor wherein amplification of the oncogenic basic helix-loop-helix (bHLH) transcription factor (TF) MYCN confers clinical and biologic features prototypical of Myc-dependent cancers. TF-dependent cancers like MYCN-amplified NB are difficult to target, but the availability of clinical-candidate transcription inhibitors makes selective blockade of oncogenic TF activity a possibility. Here we investigated whether NB could be controlled via dual targeting of the transcription elongation machinery and cell cycle progression, using an orally bioavailable and selective CDK9/2 inhibitor CYC065. CYC065 blocks nascent transcription and leads to a drastic reduction in steady-state levels of short-lived transcripts. In MYCN-amplified NB, CYC065 rapidly and completely eliminated MYCN mRNA and protein, terminating expression of a MYCN-dependent gene expression programme. This result is phenocopied by multiple clinical-candidate CDK9 chemical inhibitors and genetic manipulation of CDK9. Mechanistically, CYC065 dissociates MYCN from physical proximity of P-TEFb in cells. P-TEFb co-occupies promoters and enhancers of de-differentiating pathway genes highly-occupied by MYCN, and CDK9 inhibition terminates expression of these and other highly transcribed genes. Intriguingly, targeted inhibition of CDK9 alone is insufficient to eradicate MYCN-dependent cells lines as CDK9 loss alone is compensated by upregulation of CDK2. CYC065 targeted MYCN-driven neuroblastoma in vivo, resulted in tumor regression or eradication and prolonged survival in multiple NB models, and was effective against a wide range of Myc-dependent cancer cells lines in vitro. The data establish that combined CDK9/CDK2 inhibition blocks transcriptional dependence induced by MYCN, highlighting a potential clinical strategy by which many Myc-driven cancers could be targeted.
2019-01-01 | GSE107126 | GEO
Project description:High-risk neuroblastoma (NB) is notoriously difficult to treat and is responsible for a disproportionate number of childhood deaths due to cancer. One long accepted indicator of high-risk NB and poor prognosis is amplification of the neural MYC (MYCN) oncogene, which is currently therapeutically intractable in this patient population. The identification of Anaplastic Lymphoma Kinase (ALK) as an oncogene in NB raised the possibility of using ALK tyrosine kinase inhibitors (TKIs) in the treatment of NB patients who harbor activating ALK mutations. The number of ALK-positive NB patients on primary diagnosis is in the range of 8-10%, a figure that increases substantially in the relapsed patient population. ALK signaling is activated by the ALKAL2 ligand located on the distal portion of chromosome 2, along with the ALK receptor and MYCN loci, in the ‘2p gain’ region that has been associated with NB. The question of whether dysregulation of ALK ligand may also play a role in NB has not been addressed, although notably, one of the first oncogenes described was the v-sis oncogene that shares more than 90% homology with the PDGF ligand. Therefore, we tested whether ALKAL ligand was able to potentiate NB progression in the absence of ALK mutation. We show here that overexpression of ALKAL2 is sufficient to drive rapid onset and penetrant Th-MYCN driven NB in the absence of ALK mutation, and that these tumours are sensitive to ALK TKI therapy. These results suggest that additional NB patients, such as those exhibiting 2p gain, may also benefit from ALK TKI based therapeutic intervention.
2020-11-25 | PXD021792 | Pride
Project description:Neuroblastoma (NB) is a childhood cancer in which the MYCN amplification is the most acknowledged marker of poor prognosis. MYCN-amplified NB cells showed to rely on both glycolysis and oxidative phosphorylation system (OXPHOS) for energy production . Previously, we revealed that a ketogenic diet (KD) slowed the tumor growth in MYCN NB xenografts, when combined with classical cytotoxic therapy cyclophosphamide (CP). Metformin (MET) is a compound that targets complex I of the OXPHOS system. Therefore, the aim of this study was to elucidate whether MET can enhance the anti-tumorigenic effects of a KD in NB. Our result indicated that MET decreasedcell proliferation andrespiration in NB cells in vitro. The combination of KD, MET and low dose of chemotherapyreduced also the tumor growth and improved survival in NB xenografts. GO enrichment analysis revealed fatty acid ß-oxidation as the most upregulated process resulting from the addition of MET to KD. The differential expression of CPT1A and of its direct regulator ACC might determine an unbalanced redox state and dictate the anti-tumor effect of the combination therapy in MYCN-amplified xenografts.
2024-09-30 | GSE236677 | GEO
Project description:<p>Neuroblastoma is the most common extra-cranial solid tumor in children. It represents 8% to 10% of all childhood cancers. Stage 4 Neuroblastoma is characterized by its clinical heterogeneous outcome. The special category, stage 4S tumors (2-5% of all NB) are chemo-sensitive, and the patients show spontaneous regression. On the other hand, MYCN amplification (25-30% of all NB) is associated with poor outcome of neuroblastoma, thus we further categorize stage 4 neuroblastoma into MYCN non-amplified and MYCN amplified group. Here we use transcriptome sequencing to characterize the transcriptome in 29 stage 4 Neuroblastoma samples.</p>
| phs000868 | dbGaP
Project description:MYCN amplification (MNA) is a defining feature of high-risk neuroblastoma (NB) that predicts poor prognosis. However, whether genes within or in close proximity to the MYCN amplicon also contribute to aggressiveness in MNA+ NB remains poorly understood. Here we identify that GREB1, a transcription factor encoding gene neighboring the MYCN locus, is frequently co-expressed with MYCN, and promotes cell survival in MNA+ NB. GREB1 controls gene expression independently of MYCN in MNA+ NB, among which we uncover Myosin 1B (MYO1B) as being highly expressed in MNA+ NB. MYO1B promotes aggressive features, including invasive capacity in vitro, as well as extravasation and distant metastasis in vivo. Global secretome and proteome profiling further delineate MYO1B as a major regulator of secretome reprogramming in MNA+ NB cells. Moreover, we identify the cytokine MIF as an important pro-invasive and pro-metastatic mediator of MYO1B activity. Together, we have identified a putative GREB1-MYO1B-MIF axis as an unconventional mechanism that promotes the aggressiveness of MNA+ NB, and independently of MYCN. Furthermore, we find that MYO1B is upregulated in association with other oncoproteins during cellular transformation, and is dramatically increased in multiple human cancer types, suggesting a crucial role of MYO1B in cancers in addition to MNA+ NB.
2023-10-24 | PXD039410 | Pride