Pre-clinical spheroid models identify BMX as a therapeutic target for metastatic MYCN non-amplified neuroblastoma
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PROVIDER: PRJNA928774 | ENA |
REPOSITORIES: ENA
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Project description:The development of targeted therapies has provided new hope for an increasing number of cancer patients affected by previously incurable diseases. The clinical success of this approach, however, is limited by numerous challenges, including a better control of cell plasticity, particularly in refractory and metastatic patients. Here we addressed this question in Neuroblastoma (NB), an aggressive pediatric malignancy, which remains a clinical challenge for high-risk patients. NB originates from neural crest-derived progenitors through defective differentiation programs combined with oncogenic activity due to genetic and epigenetic alterations. In order to identify critical genes responsible for tumor aggressiveness we performed combined chromatin and transcriptome analyses on matched primary xenografts, spheroids and differentiated adherent cultures, which we derived from metastatic non-MYCN amplified (nMNA) NB patients. Our approach identified the kinase BMX among the most differentially regulated genes between patient-derived xenografts and spheroids versus adherent models. We further found that BMX expression is associated with high tumor stage and poor patient survival in multiple NB transcriptomic datasets and critical to maintain the self-renewal and tumorigenic potential of NB spheroids. Moreover, we uncovered a positive correlation between BMX expression and the mesenchymal tumor cell phenotype, which was previously associated with increased chemo-resistance. Finally, we show that BMX inhibitors can readily reverse this cellular state, increase the sensitivity of NB spheroids toward standard of care chemotherapy, and reduce tumor growth in preclinical NB models. Altogether, our study identifies BMX as a novel promising therapeutic target for high-risk patients with relapsed or refractory nMNA NB tumors.
2024-06-30 | GSE223901 | GEO
Project description:The development of targeted therapies has provided new hope for an increasing number of cancer patients affected by previously incurable diseases. The clinical success of this approach, however, is limited by numerous challenges, including a better control of cell plasticity, particularly in refractory and metastatic patients. Here we addressed this question in Neuroblastoma (NB), an aggressive pediatric malignancy, which remains a clinical challenge for high-risk patients. NB originates from neural crest-derived progenitors through defective differentiation programs combined with oncogenic activity due to genetic and epigenetic alterations. In order to identify critical genes responsible for tumor aggressiveness we performed combined chromatin and transcriptome analyses on matched primary xenografts, spheroids and differentiated adherent cultures, which we derived from metastatic non-MYCN amplified (nMNA) NB patients. Our approach identified the kinase BMX among the most differentially regulated genes between patient-derived xenografts and spheroids versus adherent models. We further found that BMX expression is associated with high tumor stage and poor patient survival in multiple NB transcriptomic datasets and critical to maintain the self-renewal and tumorigenic potential of NB spheroids. Moreover, we uncovered a positive correlation between BMX expression and the mesenchymal tumor cell phenotype, which was previously associated with increased chemo-resistance. Finally, we show that BMX inhibitors can readily reverse this cellular state, increase the sensitivity of NB spheroids toward standard of care chemotherapy, and reduce tumor growth in preclinical NB models. Altogether, our study identifies BMX as a novel promising therapeutic target for high-risk patients with relapsed or refractory nMNA NB tumors.
2024-06-30 | GSE223900 | GEO
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
Project description:Pre-clinical spheroid models identify BMX as a therapeutic target for metastatic MYCN non-amplified neuroblastoma (RNA-Seq)
| PRJNA928777 | ENA
Project description:Pre-clinical spheroid models identify BMX as a therapeutic target for metastatic MYCN non-amplified neuroblastoma (ChIP-Seq)
| PRJNA928776 | ENA
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
Project description:Purpose: Identify new targets in MYCN-amplified Neuroblastoma Methods: ChIP-Seq experiments were performed on Kelly and LAN-1 neuroblastoma cells by using the following antibodies: anti-EZH2 (Cell Signaling 5246S); anti-H3K27me3 (Millipore 07-449); anti-H3K4me3 (Abcam ab8580). We evaluated the global EZH2 PRC2-dependence by identifiying direct genome-wide target genes for EZH2, H3K27me3 and H3K4me3. Results: We found that EZH2 serves a PRC2-dependent function in neuroblastoma, repressing neuronal differentiation. Moreover, EZH2-regulated genes were strongly repressed in MYCN-amplified and high-risk primary tumors. Conclusion: Our study supports testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.
2017-12-02 | GSE85430 | GEO
Project description:Targeting EZH2 in MYCN-amplified Neuroblastoma
| PRJNA338446 | ENA
Project description:AhR promotes dedifferentiation in MYCN amplified neuroblastoma
2023-10-10 | GSE224037 | GEO
Project description:Purpose: Identify new targets in MYCN-amplified Neuroblastoma Methods: Kelly and LAN-1 neuroblastoma cells were treated in duplicate with 2 uM GSK126 (Excess Biosciences M60071-2) or DMSO for 2 or 5 days. RNA was extracted from cells with the RNeasy Kit (Qiagen). RNA libraries were prepared for sequencing using standard Illumina protocols. The pool of sixteen samples was sequenced on two lanes of an Illumina HiSeq, generating single end reads of 32-76 bp length. Transcript abundance (reads and FPKM scores) at GRCh37/hg19 RefSeq gene level was computed with the Feature Counts method implemented in the Bioconductor v3.2 Rsubread package (Liao et al., 2014). Results: Pharmacological suppression of EZH2 inhibited neuroblastoma growth. Transcriptomic analysis revealed that EZH2 serves a PRC2-dependent function in neuroblastoma, repressing neural differentiation. Moreover, EZH2-regulated genes were strongly repressed in MYCN-amplified and high risk primary tumors. These observations demonstrate that MYCN upregulates EZH2 leading to inactivation of a tumor suppressor program in neuroblastoma. Conclusion: Our study supports testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.
2017-12-02 | GSE85431 | GEO