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PAR-CLIP analysis of neuroblastoma cells in response to amidino-rocaglate treatment

ABSTRACT: MYCN-amplified neuroblastoma cells exhibit upregulation of translation initiation factors as a result of MYCN-driven transcriptional amplification, including the RNA helicase eIF4A1. Here, we treated MYCN-amplified patient derived xenograft (PDX) neuroblastoma cells with a novel translation initiation inhibitor, amidino-rocaglate CMLD12824, to analyze the impact on the global pattern of eIF4A1 binding to mRNA compared to the naive condition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261761 | GEO | 2024/06/25

REPOSITORIES: GEO

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Ribosome profiling analysis of neuroblastoma cells in response to amidino-rocaglate treatment

Project description:MYCN-amplified neuroblastoma cells exhibit upregulation of translation regulation factors and ribosome biogenesis proteins as a result of MYCN-driven transcriptional amplification. Here, we treated MYCN-amplified and non-amplified neuroblastoma cells with a novel translation inhibitor, amidino-rocaglate CMLD12824, to compare the defects in translational efficiency.

2024-06-25 | GSE261760 | GEO

The Super Elongation Complex Drives Transcriptional Addiction in MYCN-amplified Neuroblastoma

Project description:MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.

2023-05-10 | PXD039332 | Pride

Quantitative proteomics and bioinformatics analyses reveal the mechanism of pan-aurora kinase inhibitor tozasertib in neuroblastoma

Project description:Neuroblastoma is the third most common pediatric cancer and is responsible for approximately 15% of all childhood cancer deaths (Maris & Matthay, 1999). In our analysis, we found that poor patient survival with increasing mRNA expression level of AURKA and AURKB in Mycn-amplified neuroblastoma. In the light of this evidence, we were able to find possibilities of existing inhibitors for therapy. According to the following experiments, we found that tozasertib, a pan-Aurora kinase inhibitor, has high therapeutic potential in neuroblastoma treatment. First, we performed in vitro experiments to reveal that tozasertib suppressed cell proliferation in multiple Mycn-amplified neuroblastoma cell lines. Next, we evaluated ex vivo not only in Mycn-amplified neuroblastoma xenograft mouse model but also TH-Mycn transgenic mouse model. The results showed that tozasertib significantly inhibited the tumor growth and prolonged the survival probability in both animal models. Finally, we explored the mechanism of tozasertib-treated tissues in two animal models by iTRAQ proteomic.

2019-09-30 | PXD007640 | Pride

Metabolic dependencies in MYCN-driven neuroblastoma

Project description:Here we sought metabolic alterations specifically associated with amplified MYCN as nodes to indirectly target the MYCN oncogene. Liquid chromatography-mass spectrometry-based proteomics identified 7 proteins consistently correlated with MYCN in proteomes from 49 neuroblastoma biopsies and 13 cell lines. Among these were phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine synthesis. MYCN associated with two regions in the PHGDH promoter, supporting transcriptional PHGDH regulation by MYCN. Pulsed stable isotope-resolved metabolomics utilizing 13C-glucose labeling demonstrated higher de novo serine synthesis in MYCN-amplified cells compared to cells with diploid MYCN. An independence of MYCN-amplified cells from exogenous serine and glycine was demonstrated by serine and glycine starvation, which attenuated nucleotide pools and proliferation only in cells with diploid MYCN but did not diminish these endpoints in MYCN-amplified cells. Proliferation was attenuated in MYCN-amplified cells by CRISPR/Cas9-mediated PHGDH knockout or treatment with PHGDH small molecule inhibitors without affecting cell viability. PHGDH inhibitors administered as single-agent therapy to NMRI-Foxn1nu/nu mice harboring patient-derived MYCN-amplified neuroblastoma xenografts slowed tumor growth. However, combining a PHGDH inhibitor with the standard-of-care chemotherapy drug, cisplatin, revealed antagonism of chemotherapy efficacy in vivo. Emergence of chemotherapy resistance was confirmed in the genetic PHGDH knockout model in vitro. Altogether, PHDGH knockout and inhibition by small molecules consistently slows proliferation, but stops short of killing the cells, which then establish resistance to classical chemotherapy. Although PHGDH inhibition with small molecules has produced encouraging results in other preclinical cancer models, this approach must be considered with caution in patients with neuroblastoma.

2020-12-11 | PXD018300 | Pride

Homo sapiens

Project description:Neuroblastoma: MYCN normal vs. MYCN amplified

| PRJNA231852 | ENA

Transcriptome Sequencing of Pediatric Neuroblastoma

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

To identify transcripts that are differentially expressed in the MYCN amplified vs MYCN non-amplified cell lines using Next Generation Sequencing

Project description:The aims of this study are to compare transcripts that are differentially expressed in the MYCN amplified compare to the MYCN non-amplified neuroblastoma cell lines, in particular, long non-coding RNAs. Methods: Ribosomal depleted RNAs from six human neuroblastoma cell lines were subjected to deep sequencing, using Illumina Hiseq. Results: We identified 459 transcripts are differentially expressed betweeen the MYCN amplified and the MYCN non-amplified cell lines. Conclusions: We have identified a novel long noncoding RNA lncNB1 that is highly expressed in the MYCN amplified compared to the MYCN non-amplified cell lines.

2019-10-08 | GSE114053 | GEO

Human embryonic stem cell-derived neural crest model for neuroblastoma

Project description:Neuroblastoma is a common childhood malignant tumor of neural crest origin with remarkable heterogeneity in outcomes. Amplification of the oncogene MYCN is strongly associated with highly malignant behaviour and poor prognosis. Here, we used human ESC-derived neural crest model to recapitulate the initiation of MYCN-driven neuroblastoma and to identify MYCN downstream effectors. Our results show that induced deregulation of MYCN in human neural crest progenitor cells is sufficient to induce tumors that recapitulate the pathological and molecular features of human MYCN-amplified neuroblastoma(MNA-NB). By using this platform, we are able to identify a group of 28 genes that are associated with MYCN expression level only in MNA-NB.

2021-09-01 | GSE137975 | GEO

Genome-wide binding of MYCN protein in MYCN-amplified neuroblastoma cell lines

Project description:The MYCN locus is amplified in about half of high-risk neuroblastoma tumors. To identify genomic loci occupied by MYCN protein in the MYCN-amplified neuroblastoma cell lines NGP, Kelly and NB-1643, we performed chromatin immunoprecipitation coupled with Next-Generation Sequencing (ChIP-seq) using an anti-MYCN antibody.

2017-08-02 | GSE94782 | GEO

Gene expression analysis of BE(2)C cells treated with MYCN siRNA (MYCN1 #SI03087518)

Project description:Amplification of the MYCN oncogene predicts treatment resistance in childhood neuroblastoma. Using a MYC target gene signature that predicts poor neuroblastoma prognosis we identified the histone chaperone, FAcilitates Chromatin Transcription (FACT), as a crucial mediator of the MYC signal and a therapeutic target in the disease. FACT and MYCN expression created a forward feedback loop in neuroblastoma cells that was essential for maintaining mutual high expression. FACT inhibition by the small molecule Curaxin compound, CBL0137, markedly reduced tumor initiation and progression in vivo. CBL0137 exhibited strong synergy with chemotherapy in standard use by blocking repair of DNA damage caused by genotoxic drugs, thus creating a synthetic lethal environment in MYCN amplified neuroblastoma cells and a treatment strategy for MYCN-driven neuroblastoma

2015-11-16 | GSE71060 | GEO

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