Spatial transcriptional features of MYCN niche in liver tumorigenesis.
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ABSTRACT:
PROVIDER: PRJNA1292214 | 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. 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:Neuroblastoma is a pediatric cancer of the sympathetic nervous system. MYCN amplification is a key indicator of poor prognosis for the disease, however, mechanisms by which MYCN promotes neuroblastoma tumorigenesis are not fully understood. In this study, we analyzed global miRNA and mRNA expression profiles of tissues at different stages of tumorigenesis from TH-MYCN transgenic mice, a model of MYCN-driven neuroblastoma. Based on a Bayesian learning network model in which we compared pre-tumor ganglia from TH-MYCN+/+ mice to age-matched wild-type controls, we devised a predicted miRNA-mRNA interaction network. Among the miRNA-mRNA interactions operating during human neuroblastoma tumorigenesis, we identified that miR-204 is a tumor suppressor miRNA that inhibits a subnetwork of oncogenes strongly associated with MYCN-amplified neuroblastoma and poor patient outcome. Accordingly, we found that MYCN was bound to the miR-204 promoter and repressed miR-204 transcription, while in contrast, miR-204 directly bound MYCN mRNA and repressed MYCN expression. In support of a tumor suppressor role, miR-204 overexpression significantly inhibited neuroblastoma cell proliferation in vitro and tumorigenesis in vivo. Together these findings identify novel tumorigenic miRNA gene networks and miR-204 as a tumor suppressor that regulates MYCN expression in neuroblastoma tumorigenesis.
2018-06-01 | GSE100658 | 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
Project description:Transcriptional programs regulated by MYCN in liver tumorigenesis
| PRJNA1291076 | ENA
Project description:Cancer cell behaviour is strongly influenced by the surrounding cellular environment, making the characterization of the local tumour microenvironment (or niche) a fundamental question in tumour biology. To date, a direct investigation of the early cellular changes induced by metastatic cells within the surrounding tissue is difficult to achieve, especially at early micro-metastatic stages and for low frequency niche populations. Here we present the strategy whereby metastatic cancer cells release a cell-penetrating fluorescent protein that is efficiently taken up by neighbouring cells, allowing spatial identification of the local metastatic cellular environment within the whole tissue. Notably, this strategy can be used to follow metastatic niches from early micro-metastasis to late macro-metastasis, allowing temporal resolution. Moreover, the presence of low represented niche cells can be detected and characterized among the bulk tissue. To highlight its potential, we have used this niche-labelling strategy to study the lung metastatic environment of breast cancer cells. We uncover the presence of lung parenchymal cells within the metastatic niche where lung epithelial cells show stem cell-like features with expression of lung progenitor markers, multi-lineage differentiation potential and self-renewal activity. Moreover, lung epithelial cells can be directly perturbed by cancer cells in ex vivo co-culture assays and support their growth. In summary, here we describe a novel labelling system that enables spatial resolution of the metastatic microenvironment and provide evidence that the tissue cellular environment surrounding metastatic growth is characterized by undifferentiated features. The data highlight the significant potential of this method as a platform for new discoveries.
2019-08-21 | PXD010597 | Pride
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:Multiple distinct cell types of the human lung and airways have been defined by single cell RNA sequencing (scRNAseq). Here we present a multi-omics spatial lung atlas to define novel cell types which we map back into the macro- and micro-anatomical tissue context to define functional tissue microenvironments. Firstly, we have generated single cell and nuclei RNA sequencing, VDJ-sequencing and Visium Spatial Transcriptomics data sets from 5 different locations of the human lung and airways. Secondly, we define additional cell types/states, as well as spatially map novel and known human airway cell types, such as adult lung chondrocytes, submucosal gland (SMG) duct cells, distinct pericyte and smooth muscle subtypes, immune-recruiting fibroblasts, peribronchial and perichondrial fibroblasts, peripheral nerve associated fibroblasts and Schwann cells. Finally, we define a survival niche for IgA-secreting plasma cells at the SMG, comprising the newly defined epithelial SMG-Duct cells, and B and T lineage immune cells. Using our transcriptomic data for cell-cell interaction analysis, we propose a signalling circuit that establishes and supports this niche. Overall, we provide a transcriptional and spatial lung atlas with multiple novel cell types that allows for the study of specific tissue microenvironments such as the newly defined gland-associated lymphoid niche (GALN).
2022-01-06 | E-MTAB-11640 | biostudies-arrayexpress
Project description:An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability
| PRJNA631737 | ENA
Project description:MYCN amplification (MNA) is a defining feature of high-risk neuroblastoma (NB) that predicts poor prognosis. However, whether genes within or in close proximity to the MYCN amplicon also contribute to aggressiveness in MNA+ NB remains poorly understood. Here we identify that GREB1, a transcription factor encoding gene neighboring the MYCN locus, is frequently co-expressed with MYCN, and promotes cell survival in MNA+ NB. GREB1 controls gene expression independently of MYCN in MNA+ NB, among which we uncover Myosin 1B (MYO1B) as being highly expressed in MNA+ NB. MYO1B promotes aggressive features, including invasive capacity in vitro, as well as extravasation and distant metastasis in vivo. Global secretome and proteome profiling further delineate MYO1B as a major regulator of secretome reprogramming in MNA+ NB cells. Moreover, we identify the cytokine MIF as an important pro-invasive and pro-metastatic mediator of MYO1B activity. Together, we have identified a putative GREB1-MYO1B-MIF axis as an unconventional mechanism that promotes the aggressiveness of MNA+ NB, and independently of MYCN. Furthermore, we find that MYO1B is upregulated in association with other oncoproteins during cellular transformation, and is dramatically increased in multiple human cancer types, suggesting a crucial role of MYO1B in cancers in addition to MNA+ NB.
2023-10-24 | PXD039410 | Pride