METTL3/MYCN cooperation drives neural crest differentiation and provides therapeutic vulnerability in neuroblastoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1023241 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26263600_1.fastq.gz | Fastqsanger.gz | |||
| SRR26263600_2.fastq.gz | Fastqsanger.gz | |||
| SRR26263601_1.fastq.gz | Fastqsanger.gz | |||
| SRR26263601_2.fastq.gz | Fastqsanger.gz | |||
| SRR26263602_1.fastq.gz | Fastqsanger.gz |
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Project description:Neuroblastoma (NB) is a childhood cancer. Improper differentiation of developing trunk neural crest cells (tNCC) cause NB tumor formation in sympathetic nervous system. N6-methyladenosine (m6A) epitranscriptomic modification control post-transcriptional gene expression but the mechanism which recruit m6A methyltransferase complex to specific locus is less characterized. We explored if m6A epitranscriptome could fine tune gene regulation in migrating/differentiating tNCC. We uncovered m6A epitranscriptome based regulation of HOX gene expression in tNCC which contributes in their timely differentiation to sympathetic neurons. Posterior HOX genes are m6A modified in MYCN NB cells and tumors. We provided evidence that sustained overexpression of MYCN oncogene could drive METTL3 recruitment in subset of genes to create an undifferentiated state in tNCC. Our study suggests oncogenic transcription factor mediated modulation of m6A epitranscriptome could be a prevalent mechanism in other cancers. METTL3 depletion/inhibition induces DNA damage and differentiation in MYCN overexpressed cells. METTL3 inhibition increases vulnerability to the chemotherapeutic drug in MYCN-amplified Patient-derived xenografts (PDX) cells, suggesting METTL3 inhibition could be a potential therapeutic approach for NB.
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Project description:Neuroblastoma (NB) is the most common extracranial childhood cancer, caused by the improper differentiation of developing trunk neural crest cells (tNCC) in the sympathetic nervous system. The N6-methyladenosine (m6A) modification controls post-transcriptional gene expression but the mechanism by which the m6A methyltransferase complex METTL3/METTL14/WTAP is recruited to specific loci remains to be fully characterized. We explored whether the m6A epitranscriptome could fine-tune gene regulation in migrating/differentiating tNCCs. We demonstrate that the m6A modification regulates the expression of HOX genes in tNCCs, thereby contributing to their timely differentiation into sympathetic neurons. Furthermore, we show that posterior HOX genes are m6A-modified in MYCN-amplified neuroblastoma with reduced expression. In addition, we provide evidence that sustained overexpression of the MYCN oncogene in tNCC drives METTL3 recruitment to a specific subset of genes including posterior HOX genes, creating an undifferentiated state. Moreover, METTL3 depletion or inhibition induces DNA damage and differentiation of MYCN-overexpressing cells and increases vulnerability to chemotherapeutic drugs in MYCN-amplified patient-derived xenografts in vivo, suggesting METTL3 inhibition as a potential therapeutic approach for NB.
| S-SCDT-10_1038-S44318-024-00299-8 | biostudies-other
Project description:Neuroblastoma (NB) is the most common extracranial childhood cancer, caused by the improper differentiation of developing trunk neural crest cells (tNCC) in the sympathetic nervous system. The N6-methyladenosine (m6A) epitranscriptomic modification controls post-transcriptional gene expression but the mechanism by which the m6A methyltransferase complex METTL3/METTL14/WTAP is recruited to specific loci remains to be fully characterized. We explored whether the m6A epitranscriptome could fine-tune gene regulation in migrating/differentiating tNCC. We demonstrate that the m6A modification regulates the expression of HOX genes in tNCC, thereby contributing to their timely differentiation into sympathetic neurons. Furthermore, we show that posterior HOX genes are m6A modified in MYCN-amplified NB with reduced expression. In addition, we provide evidence that sustained overexpression of the MYCN oncogene in tNCC drives METTL3 recruitment to a specific subset of genes including posterior HOX genes creating an undifferentiated state. Moreover, METTL3 depletion/inhibition induces DNA damage and differentiation of MYCN overexpressing cells and increases vulnerability to chemotherapeutic drugs in MYCN-amplified patient-derived xenografts (PDX) in vivo, suggesting METTL3 inhibition could be a potential therapeutic approach for NB.
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Project description:The ALK^F1174L mutation is associated with intrinsic and acquired resistance to crizotinib and cosegregates with MYCN in neuroblastoma. In this study, we generated a mouse model overexpressing ALK^F1174L in the neural crest. Comapred to mice expressing ALK^F1174L or MYCN alone, combined expression of the two aberrations led to development of neuroblastoma with a shorter latency and higher penetrance. Here, we evaluated the transcriptional profiles of MYCN-driven neuroblastomas with or without the expression of ALK^F1174L to determine the pathogenic consequences of the ALK^F1174L/MYCN interaction in neuroblastoma. 10 mice were analysed in this study. Five ALK^F1174L/MYCN tumors were compared with five MYCN tumors. Total RNA was extracted, samples were labeled and processed using the Agilent Low Input Quick Amp two color Cy3(sample) and Cy5 (mouse reference) labeling kit and hybridized to Agilent SurePrint G3 Mouse Gene Expression arrays.
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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.
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Project description:Amplification of MYCN is the most prominent genetic marker of high-stage neuroblastoma, a childhood tumor originating from the neural crest. We generated a transgenic mouse with Cre-conditional induction of MYCN in dopamine beta hydroxylase expressing cells that develops murine neuroblastomas.
2014-09-01 | GSE51297 | GEO
Project description:The ALK^F1174L mutation is associated with intrinsic and acquired resistance to crizotinib and cosegregates with MYCN in neuroblastoma. In this study, we generated a mouse model overexpressing ALK^F1174L in the neural crest. Comapred to mice expressing ALK^F1174L or MYCN alone, combined expression of the two aberrations led to development of neuroblastoma with a shorter latency and higher penetrance. Here, we evaluated the transcriptional profiles of MYCN-driven neuroblastomas with or without the expression of ALK^F1174L to determine the pathogenic consequences of the ALK^F1174L/MYCN interaction in neuroblastoma.
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