Trajectory analysis reveals an uncommitted neuroblastic state in MYCN-driven neuroblastoma development
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PROVIDER: PRJNA1040130 | ENA |
REPOSITORIES: ENA
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Project description:We analyzed the transcriptomic features of spontaneous regression in pre-cancerous neuroblasts using Th-MYCN mice, an animal model that closely resembles human neuroblastoma. Single-cell transcriptomic analysis of ganglion tissues from Th-MYCN mice was conducted to elucidate the cellular and molecular underpinnings. Trajectory analysis of pre-cancerous neuroblasts revealed a distinct subtype we designated as "uncommitted" cells, characterized by the expression of neuronal genes, indicative of a semi-differentiated state. Samples with predicted failed tumorigenesis had a greater proportion of these uncommitted cells, hinting at their association with spontaneous regression.
2025-07-02 | GSE247665 | GEO
Project description:Neuroblastoma 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 neuroblastoma 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 order to gain further insight into the role of gene expression during neuroblastoma initiation and progression, we evaluated gene expression profiles of hyperplastic ganglia and tumors isolated from MYCN transgenic mice.
2016-02-28 | E-MTAB-3247 | biostudies-arrayexpress
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
Project description:Changes in epigenetic regulation are believed to be a major contributing factor to neuroblastoma development. Using a large-scale in vivo mutagenesis screen in Th-MYCN transgenic mice, we identified a single point mutation in the transcriptional corepressor Runx1t1, that can block N-myc-driven neuroblastoma tumorigenesis. The loss of function mutation disrupts a highly conserved zinc finger domain (NHR4) within Runx1t1. Crossing an independent Runx1t1 knockout model with Th-MYCN mice, demonstrated that Runx1t1 haploinsufficiency is enough to prevent neuroblastoma development and reverse ganglia hyperplasia. Silencing RUNX1T1 in human neuroblastoma cells resulted in decreased colony formation in vitro, and significant inhibition of tumor growth in vivo. Our results show that RUNX1T1 forms part of a transcriptional LSD1-CoREST3-HDAC repressive complex that regulates the epigenomic landscape and chromatin accessibility, to control neuron-specific pathway genes and maintain an undifferentiated state. Runx1t1 thus represents an entirely novel and highly promising target not previously described in neuroblastoma.
2024-08-10 | PXD050375 | Pride
Project description:ALK is a tyrosine kinase receptor and oncogene in neuroblastoma (NB). The receptor is activated by the ALKAL2 ligand, but it is unknown whether missregulation of this ligand may play a role in NB carcinogenesis. Here, a TH-MYCN driven neuroblastoma mice was created +/- ALK F1178S mutation and +/- ALKAL2 overexpression
2020-11-24 | E-MTAB-9600 | biostudies-arrayexpress
Project description:The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a paediatric cancer in which MYCN amplification is strongly associated with unfavourable outcome. Here, we show that CYC065, a clinical inhibitor of CDK2 and CDK9, selectively targets MYCN-amplified neuroblastoma via blockade of CDK9-dependent, MYCN-driven transcriptional elongation and CDK2-dependent proliferation. CYC065 also targets nascent transcription of short half-life genes including MYCN and MCL-1 leading to downregulation of MYCN-driven ‘adrenergic’ gene expression programs, growth inhibition, and apoptosis in vitro and in vivo. These data highlight the clinical potential of CDK2/9 inhibition in the treatment of MYCN-amplified neuroblastoma.
2020-10-13 | GSE128330 | GEO
Project description:The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a paediatric cancer in which MYCN amplification is strongly associated with unfavourable outcome. Here, we show that CYC065, a clinical inhibitor of CDK2 and CDK9, selectively targets MYCN-amplified neuroblastoma via blockade of CDK9-dependent, MYCN-driven transcriptional elongation and CDK2-dependent proliferation. CYC065 also targets nascent transcription of short half-life genes including MYCN and MCL-1 leading to downregulation of MYCN-driven ‘adrenergic’ gene expression programs, growth inhibition, and apoptosis in vitro and in vivo. These data highlight the clinical potential of CDK2/9 inhibition in the treatment of MYCN-amplified neuroblastoma.
2020-10-13 | GSE145068 | 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:GAS7 Deficiency Promotes Metastasis of MYCN-driven Neuroblastoma
| PRJNA543225 | ENA
Project description:The RET gene has been identified previously as a target of activated ALK at the mRNA level in both human neuroblastoma cell lines and primary tumors as well as in murine tumors driven by mutated Alk and MYCN. Moreover, it has been shown that tumor growth of murine TH-MYCN/KI Alkmut tumors was impaired upon Ret inhibition by the vandetanib inhibitor, suggesting RET as a therapeutic target in ALK mutated neuroblastoma. To further demonstrate the crucial role of RET in ALK mutated driven neuroblastoma oncogenesis, transgenic TH-MYCN mice were bred with KI RetM919T tumors. We document an oncogenic cooperation between activated Ret and MYCN overexpression in neuroblastoma formation. We used microarrays to analyze the global programme of gene expression of MYCN/RetM919T tumors and compare these profiles with profiles of MYCN/Alkmut tumors (GSE46583). Altogether, our data show that MYCN/RetM919T tumors present with expression profiles close to MYCN/Alkmut tumors.
2017-09-15 | GSE72678 | GEO