Transcriptional landscape of MYCN-driven liver tumors
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ABSTRACT:
PROVIDER: PRJNA1290112 | ENA |
REPOSITORIES: ENA
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Project description:Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death, often diagnosed at advanced stages and characterized by high recurrence rates. While chronic liver inflammation and metabolic dysfunction are recognized contributors to tumorigenesis, the molecular mechanisms linking early microenvironmental stress to malignant transformation remain poorly understood. MYCN, a proto-oncogenic transcription factor, has emerged as a potential biomarker of cancer stemness, yet its functional role in hepatocarcinogenesis is unclear. Here, we elucidate the oncogenic role of MYCN and its dynamic regulation during metabolic liver tumorigenesis.Using a transposon system in mice and the human hepatocyte cell line Hc, we demonstrate that MYCN overexpression functionally promotes liver tumorigenesis and hepatocyte transformation. Transcriptomic profiling of MYCN-driven tumors revealed molecular features resembling human HCC subtypes enriched in stress-adaptive gene programs, highlighting MYCN's role in shaping tumor-promoting transcriptional landscapes.
2025-07-16 | GSE302338 | 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. 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.
2012-07-04 | E-GEOD-35560 | biostudies-arrayexpress
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:Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death, often diagnosed at advanced stages and characterized by high recurrence rates. While chronic liver inflammation and metabolic dysfunction are recognized contributors to tumorigenesis, the molecular mechanisms linking early microenvironmental stress to malignant transformation remain poorly understood. MYCN, a proto-oncogenic transcription factor, has emerged as a potential biomarker of cancer stemness, yet its functional role in hepatocarcinogenesis is unclear. Here, we elucidate the oncogenic role of MYCN and its dynamic regulation during metabolic liver tumorigenesis. Transcriptomic profiling revealed that MYCN-driven tumors exhibit features of human HCC subtypes enriched in stress-adaptive transcriptional programs. Time-resolved spatial transcriptomics further uncovered a MYCN-enriched niche characterized by epithelial–mesenchymal transition (EMT) and Wnt/β-catenin signaling, which expanded during tumor progression and was spatially proximate to transformed malignant cells.
2025-07-30 | GSE302815 | GEO
Project description:Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death, often diagnosed at advanced stages and characterized by high recurrence rates. While chronic liver inflammation and metabolic dysfunction are recognized contributors to tumorigenesis, the molecular mechanisms linking early microenvironmental stress to malignant transformation remain poorly understood. MYCN, a proto-oncogenic transcription factor, has emerged as a potential biomarker of cancer stemness, yet its functional role in hepatocarcinogenesis is unclear. Here, we applied CUT&RUN-seq analysis and integrated the data with RNA-seq to investigate the direct transcriptional impact of MYCN in liver tumorigenesis. Transcriptomic profiling revealed that MYCN-driven tumors exhibit features of human HCC subtypes enriched in stress-adaptive gene programs. We found genes with upstream MYCN binding showed significantly greater expression changes between tumor and non-tumor samples, suggesting that MYCN binding in promoter-proximal regions has a stronger influence on transcriptional regulation. Pathway analysis revealed significant enrichment in pathways related to cytoskeletal organization, cell motility, and membrane dynamics, all of which are central to intercellular interactions and tumor microenvironment remodeling, indicating that MYCN regulates pathways contributing to tumor microenvironment remodeling and cellular interactions.
2025-07-19 | GSE302484 | GEO
Project description:Retinoblastoma are childhood eye tumors arising from retinal precursor cells. Two distinct retinoblastoma subtypes with different clinical behavior have been described based on gene expression and methylation profiling. Using consensus clustering of DNA methylation analysis from retinoblastomas, we identified a MYCN-driven cluster of subtype 2 retinoblastomas characterized by DNA hypomethylation and high expression of genes involved in protein synthesis. Subtype 2 retinoblastomas outside the MYCN-driven cluster were characterized by high expression of genes from mesodermal development, including NKX2-5. Knockdown of MYCN expression in retinoblastoma cell models caused growth arrest and reactivated a subtype 1-specific photoreceptor signature. These molecular changes suggest that removing the driving force of MYCN oncogenic activity rescues molecular circuitry driving subtype 1 biology. The MYCN-RB gene signature generated from the cell models better identified MYCN-driven retinoblastoma than MYCN amplification and could identify cases that may benefit from MYCN-targeted therapy. MYCN drives tumor progression in a molecularly defined retinoblastoma subgroup, and inhibiting MYCN activity could restore a more differentiated and less aggressive tumor biology
2024-05-31 | GSE267015 | GEO
Project description:Retinoblastoma are childhood eye tumors arising from retinal precursor cells. Two distinct retinoblastoma subtypes with different clinical behavior have been described based on gene expression and methylation profiling. Using consensus clustering of DNA methylation analysis from retinoblastomas, we identified a MYCN-driven of subtype 2 retinoblastomas characterized by DNA hypomethylation and high expression of genes involved in protein synthesis. Subtype 2 retinoblastomas outside the MYCN-driven were characterized by high expression of genes from mesodermal development, including NKX2-5. Knockdown of MYCN expression in retinoblastoma cell models caused growth arrest and reactivated a subtype 1-specific photoreceptor signature. These molecular changes suggest that removing the driving force of MYCN oncogenic activity rescues molecular circuitry driving subtype 1 biology. The MYCN-RB gene signature generated from the cell models better identified MYCN-driven retinoblastoma than MYCN amplification and could identify cases that may benefit from MYCN-targeted therapy. MYCN drives tumor progression in a molecularly defined retinoblastoma subgroup, and inhibiting MYCN activity could restore a more differentiated and less aggressive tumor biology
2024-05-31 | GSE268136 | GEO
Project description:MYCN overexpression is a hallmark of many tumors originating from neural cell precursors. We generated a transgenic mouse with Cre-conditional induction of MYCN in glial fibre acidic protein (GFAP) expressing cells resulting in the development of neuroendocrine tumors of the pancreas and the brain. The expression profiles of nine tumors from pancreas and three brain tumors were compared to non-malignant pancreas controls (GSM771025.CEL-GSM771027.CEL) from wildtype mice Expression profiles of tumors and controls were analysed using GSEA and ANOVA.
2016-03-01 | E-GEOD-73466 | biostudies-arrayexpress
Project description:Deregulation of the MYCN gene drives the development of neuronal and neuroendocrine tumors and is often associated with a particularly poor prognosis. Here we show that activation of MYCN in human neuroblastoma cells induces promoter escape of RNAPII. If pause release of RNAPII fails, MYCN recruits the BRCA1 protein to promoter-proximal regions. Recruitment of BRCA1 prevents MYCN-dependent accumulation of stalled RNAPII and enhances transcriptional activation by MYCN. Mechanistically, BRCA1 stabilizes mRNA de-capping complexes and enables MYCN to suppress R-loop formation in promoter-proximal regions. Recruitment of BRCA1 is mediated by the ubiquitin-specific protease, USP11, which binds specifically to MYCN that is de-phosphorylated at Thr58. Thr58 phosphorylation promotes proteasomal turnover of MYCN, hence BRCA1 stabilizes chromatin association of MYCN. Since BRCA1 is highly expressed in neuronal progenitor cells during early development and since MYC is less efficient than MYCN in recruiting BRCA1, our findings argue that a cell lineage-specific stress response enables MYCN-driven tumors to cope with deregulated RNAPII function.
2019-03-21 | GSE111905 | GEO
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