scholarly journals Wnt signalling is a major determinant of neuroblastoma cell lineages

2018 ◽  
Author(s):  
Marianna Szemes ◽  
Alexander Greenhough ◽  
Karim Malik
Keyword(s):  
Neural Crest ◽  
Regulatory Networks ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Wnt Signalling ◽  
Major Determinant ◽  
Next Generation Sequencing Data ◽  
Sequencing Data ◽  
Cell Lineages ◽  
And Migration

AbstractThe neural crest, which has been referred to as the fourth germ layer, comprises a multipotent cell population which will specify diverse cells and tissues, including craniofacial cartilage and bones, melanocytes, the adrenal medulla and the peripheral nervous system. These cell fates are known to be determined by gene regulatory networks (GRNs) acting at various stages of neural crest development, such as induction, specification, and migration. Although transcription factor hierarchies and some of their interplay with morphogenetic signalling pathways have been characterised, the full complexity of activities required for regulated development remains uncharted. Deregulation of these pathways may contribute to tumourigenesis, as in the case of neuroblastoma, a frequently lethal embryonic cancer thought to arise from the sympathoadrenal lineage of the neural crest.In this conceptual analysis, we utilise next generation sequencing data from neuroblastoma cells and tumours to evaluate the possible influences of Wnt signalling on neural crest GRNs and on neuroblastoma cell lineages. We provide evidence that Wnt signalling is a major determinant of regulatory networks that underlie mesenchymal/NCC-like cell identities through PRRX1 and YAP/TAZ transcription factors. Furthermore, Wnt may also co-operate with Hedgehog signalling in driving proneural differentiation programmes along the adrenergic lineage. We propose that elucidation of Signalling Regulatory Networks can augment and complement GRNs in characterising cell identities, which will in turn contribute to the design of improved therapeutics tailored to primary and relapsing neuroblastoma.

scholarly journals Learning gene regulatory networks from next generation sequencing data

Biometrics ◽  
2017 ◽  
Vol 73 (4) ◽  
pp. 1221-1230 ◽  
Author(s):  
Bochao Jia ◽  
Suwa Xu ◽  
Guanghua Xiao ◽  
Vishal Lamba ◽  
Faming Liang
Keyword(s):  
Next Generation Sequencing ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Next Generation Sequencing Data ◽  
Next Generation ◽  
Sequencing Data ◽  
Gene Regulatory ◽  
Generation Sequencing

scholarly journals Integrative genomics identifies lncRNA regulatory networks across 1,044 pediatric leukemias and solid tumors

2020 ◽  
Author(s):  
Apexa Modi ◽  
Gonzalo Lopez ◽  
Karina L. Conkrite ◽  
Tsz Ching Leung ◽  
Sathvik Ramanan ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Neuroblastoma Cells ◽  
Integrative Genomics ◽  
Sequencing Data ◽  
Specific Expression ◽  
Pediatric Leukemia ◽  
Lncrna Expression ◽  
Pediatric Cancers

AbstractLong non-coding RNAs (lncRNAs) play an important role in gene regulation and can contribute to tumorigenesis. While pan-cancer studies of lncRNA expression have been performed for adult malignancies, the lncRNA landscape across pediatric cancers remains largely uncharted. Here, we curate RNA sequencing data for 1,044 pediatric leukemia and solid tumors and integrate paired tumor whole genome sequencing and epigenetic data in relevant cell line models to explore lncRNA expression, regulation, and association with cancer. We report a total of 2,657 robustly expressed lncRNAs across six pediatric cancers, including 1,142 lncRNAs exhibiting histotype-specific expression. DNA copy number alterations contributed to lncRNA dysregulation at a proportion comparable to protein coding genes. Analysis of upstream regulation via tissue-specific, oncogenic transcription factors further implicated 608 distinct histotype-associated lncRNAs. Application of a multi-dimensional framework to identify and prioritize lncRNAs impacting entire gene networks revealed that lncRNAs dysregulated in pediatric cancer are associated with proliferation, metabolism, and DNA damage pathways. Silencing TBX2-AS1, the top-prioritized neuroblastoma-specific lncRNA, resulted in significant growth inhibition of neuroblastoma cells. Taken together, these data provide a comprehensive characterization of lncRNA regulation and function in pediatric cancers and pave the way for hypothesis-driven mechanistic studies.

RB2/p130 ectopic gene expression in neuroblastoma stem cells: evidence of cell-fate restriction and induction of differentiation

2001 ◽  
Vol 360 (3) ◽  
pp. 569-577 ◽  
Author(s):  
Francesco P. JORI ◽  
Umberto GALDERISI ◽  
Elena PIEGARI ◽  
Gianfranco PELUSO ◽  
Marilena CIPOLLARO ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Neural Crest ◽  
Cell Fate ◽  
Neuroblastoma Cell ◽  
Ectopic Expression ◽  
Neuroblastoma Cells ◽  
Lineage Specification ◽  
Ectopic Gene Expression ◽  
Neuronal Lineage ◽  
Fate Restriction

The activity of the RB2/p130 gene, which is a member of the retinoblastoma gene family, is cell-cycle-regulated and plays a key role in growth inhibition and differentiation. We used neuroblastoma cell lines as a model for studies on neural crest progenitor cell differentiation. We show that Rb2/p130 ectopic protein expression induces morphological and molecular modifications, promoting differentiation of intermediate (I) phenotype SK-N-BE(2)-C neuroblastoma cells towards a neuroblastic (N) rather than a Schwann/glial/melanocytic (S) phenotype. These modifications are stable as they persist even after treatment with an S-phenotype inducer. Rb2/p130 ectopic expression also induces a more differentiated phenotype in N-type SH-SY-5Y cells. Further, this function appears to be independent of cell-cycle withdrawal. The data reported suggest that the Rb2/p130 protein is able to induce neuronal lineage specification and differentiation in neural crest stem and committed neuroblastoma cells, respectively. Thus, the Rb2/p130 protein seems to be required throughout the full neural maturation process.

scholarly journals TopicNet: a framework for measuring transcriptional regulatory network change

2019 ◽  
Author(s):  
Shaoke Lou ◽  
Tianxiao Li ◽  
Xiangmeng Kong ◽  
Jing Zhang ◽  
Jason Liu ◽  
...  
Keyword(s):  
Regulatory Network ◽  
Regulatory Networks ◽  
Large Scale ◽  
Latent Dirichlet Allocation ◽  
Transcriptional Regulatory Network ◽  
Network Connectivity ◽  
Next Generation Sequencing Data ◽  
Sequencing Data ◽  
Differential Survival ◽  
Network Change

SummaryNext generation sequencing data highlights comprehensive and dynamic changes in the human gene regulatory network. Moreover, changes in regulatory network connectivity (network “rewiring”) manifest different regulatory programs in multiple cellular states. However, due to the dense and noisy nature of the connectivity in regulatory networks, directly comparing the gains and losses of targets of key TFs is not that informative. Thus, here, we seek a abstracted lower-dimensional representation to understand the main features of network change. In particular, we propose a method called TopicNet that applies latent Dirichlet allocation (LDA) to extract meaningful functional topics for a collection of genes regulated by a TF. We then define a rewiring score to quantify the large-scale changes in the regulatory network in terms of topic change for a TF. Using this framework, we can pinpoint particular TFs that change greatly in network connectivity between different cellular states. This is particularly relevant in oncogenesis. Also, incorporating gene-expression data, we define a topic activity score that gives the degree that a topic is active in a particular cellular state. Furthermore, we show how activity differences can highlight differential survival in certain cancers.

scholarly journals AQP1 Is Up-Regulated by Hypoxia and Leads to Increased Cell Water Permeability, Motility, and Migration in Neuroblastoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Zihe Huo ◽  
Mihai Lomora ◽  
Urs Kym ◽  
Cornelia Palivan ◽  
Stefan G. Holland-Cunz ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Water Permeability ◽  
Cell Structure ◽  
Neuroblastoma Cell ◽  
Water Channel ◽  
Neuroblastoma Cells ◽  
Hypoxic Conditions ◽  
Aqp1 Expression ◽  
And Migration ◽  
Neuroblastoma Cell Lines

The water channel aquaporin 1 (AQP1) has been implicated in tumor progression and metastasis. It is hypothesized that AQP1 expression can facilitate the transmembrane water transport leading to changes in cell structure that promote migration. Its impact in neuroblastoma has not been addressed so far. The objectives of this study have been to determine whether AQP1 expression in neuroblastoma is dependent on hypoxia, to demonstrate whether AQP1 is functionally relevant for migration, and to further define AQP1-dependent properties of the migrating cells. This was determined by investigating the reaction of neuroblastoma cell lines, particularly SH-SY5Y, Kelly, SH-EP Tet-21/N and SK-N-BE(2)-M17 to hypoxia, quantitating the AQP1-related water permeability by stopped-flow spectroscopy, and studying the migration-related properties of the cells in a modified transwell assay. We find that AQP1 expression in neuroblastoma cells is up-regulated by hypoxic conditions, and that increased AQP1 expression enabled the cells to form a phenotype which is associated with migratory properties and increased cell agility. This suggests that the hypoxic tumor microenvironment is the trigger for some tumor cells to transition to a migratory phenotype. We demonstrate that migrating tumor cell express elevated AQP1 levels and a hypoxic biochemical phenotype. Our experiments strongly suggest that elevated AQP1 might be a key driver in transitioning stable tumor cells to migrating tumor cells in a hypoxic microenvironment.

scholarly journals GSK3 Controls Migration of the Neural Crest Lineage

2018 ◽  
Author(s):  
Sandra G. Gonzalez Malagon ◽  
Anna M. Lopez Muñoz ◽  
Daniel Doro ◽  
Triòna G. Bolger ◽  
Evon Poon ◽  
...  
Keyword(s):  
Cell Migration ◽  
Neural Crest ◽  
Glycogen Synthase ◽  
Neuroblastoma Cells ◽  
Neural Crest Cells ◽  
Anaplastic Lymphoma ◽  
Neural Crest Development ◽  
And Migration ◽  
Neural Crest Migration

AbstractMigration of the neural crest lineage is critical to its physiological function. Mechanisms controlling neural crest migration are comparatively unknown, due to difficulties accessing this cell population in vivo. Here, we uncover novel requirements of glycogen synthase kinase 3 (GSK3) in regulating the neural crest. We demonstrate that GSK3 is tyrosine phosphorylated (pY) in neural crest cells and that this activation depends on anaplastic lymphoma kinase (ALK), a protein associated with neuroblastoma. Consistent with this, neuroblastoma cells with pathologically increased ALK activity express high levels of pY-GSK3 and migration of these cells can be inhibited by GSK3 or ALK blockade. In normal neural crest cells, loss of GSK3 leads to increased pFAK and misregulation of Rac1 and lamellipodin, key regulators of cell migration. Genetic reduction of GSK-3 results in failure of migration. All together, this work identifies a role for GSK3 in cell migration during neural crest development and cancer.

scholarly journals Epigenetic state determines inflammatory sensing in neuroblastoma

2021 ◽  
Author(s):  
Adam J. Wolpaw ◽  
Liron D. Grossmann ◽  
May M. Dong ◽  
Jessica L. Dessau ◽  
Patricia A. Brafford ◽  
...  
Keyword(s):  
Cell Lines ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Sequencing Data ◽  
Inflammatory Signaling ◽  
Human Neuroblastoma ◽  
Epigenetic State ◽  
Inflammatory Stimuli ◽  
Inflammatory State

AbstractImmunotherapy has revolutionized cancer treatment, but many cancers are not impacted by currently available immunotherapeutic strategies. Here, we investigated inflammatory signaling pathways in neuroblastoma, a classically “cold” pediatric cancer. By testing the functional response of a panel of 20 diverse neuroblastoma cell lines to three different inflammatory stimuli, we found that all cell lines have intact interferon signaling and all but one lack functional cGAS-STING signaling. However, toll-like receptor (TLR) signaling, particularly through TLR3, was heterogeneous. Six cell lines showed robust response, five of which are in the mesenchymal epigenetic state, while all 14 unresponsive cell lines are in the adrenergic state. Genetically switching the adrenergic BE2(c) cell line towards the mesenchymal state fully restored TLR responsiveness. In responsive cells, TLR3 activation results in the secretion of pro-inflammatory cytokines, enrichment of inflammatory transcriptomic signatures, and increased tumor killing by T-cells in vitro. Using single cell RNA sequencing data, we show that human neuroblastoma cells with stronger mesenchymal signatures have a higher basal inflammatory state, demonstrating intra-tumoral heterogeneity in inflammatory signaling that has significant implications for immunotherapeutic strategies in this aggressive childhood cancer.

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