A5003346532- Neuroblastoma Research and Treatments
- Cancer, Hypoxia, and Metabolism
- Cancer-related Molecular Pathways
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- Signaling Pathways in Disease
- Mitochondrial Function and Pathology
- FOXO transcription factor regulation
- High Altitude and Hypoxia
- Computational Drug Discovery Methods
- Ferroptosis and cancer prognosis
- Neuroscience of respiration and sleep
- Bioinformatics and Genomic Networks
- Cancer therapeutics and mechanisms
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- Virus-based gene therapy research
- Physiological and biochemical adaptations
- Genomic variations and chromosomal abnormalities
- Cancer Genomics and Diagnostics
- Zebrafish Biomedical Research Applications
- Chromatin Remodeling and Cancer
- Ocular Oncology and Treatments
- Genomics and Chromatin Dynamics
National Center for Tumor Diseases
2021
Hopp Children's Cancer Center Heidelberg
2020-2021
Heidelberg University
2011-2021
German Cancer Research Center
2011-2021
DKFZ-ZMBH Alliance
2016
University Hospital Heidelberg
2011-2015
The Kinghorn Cancer Centre
2015
Garvan Institute of Medical Research
2015
University Hospital Cologne
2015
Johannes Gutenberg University Mainz
2012-2014
Patient-specific modeling of a cell death–promoting pathway may lead to personalized treatment strategies.
The broad clinical spectrum of neuroblastoma ranges from spontaneous regression to rapid progression despite intensive multimodal therapy. This diversity is not fully explained by known genetic aberrations, suggesting the possibility epigenetic involvement in pathogenesis. In pursuit this hypothesis, we took an integrative approach analyze methylomes, transcriptomes, and copy number variations 105 cases neuroblastoma, complemented primary tumor- cell line-derived global histone modification...
Abstract Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that is a constituent of the recently established core regulatory circuitry with features cell identity factor, driving proliferation through activation p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2...
Suppression of p53 activity is essential for proliferation and survival tumor cells. A direct p53-activating compound, nutlin-3, was used in this study, together with mutation analysis, to characterize pathway defects a set 34 human neuroblastoma cell lines. We identified 9 lines (26%) loss-of-function mutation, including 6 missense mutations, 1 nonsense in-frame deletion, homozygous deletion the 3' end gene. Sensitivity nutlin-3 highly predictive absence mutation. Signaling pathways...
Relapse with drug-resistant disease is the main cause of death in MYCN-amplified neuroblastoma patients. cells vitro are characterized by a failure to arrest at G(1)-S checkpoint after irradiation- or drug-induced DNA damage. We show that several cell lines harbor additional chromosomal aberrations targeting p53 and/or pRB pathway components, including CDK4/CCND1/MDM2 amplifications, p16INK4A/p14ARF deletions TP53 mutations. Cells these undergo significantly lower levels doxorubicin...
Neuroblastoma is an embryonal pediatric tumor that originates from the developing sympathetic nervous system and shows a broad range of clinical behavior, ranging fatal progression to differentiation into benign ganglioneuroma. In experimental neuroblastoma systems, retinoic acid (RA) effectively induces neuronal differentiation, RA treatment has been therefore integrated in current therapies. However, molecular mechanisms underlying are still poorly understood. We here investigated role...
Uncontrolled cell cycle entry, resulting from deregulated CDK-RB1-E2F pathway activity, is a crucial determinant of neuroblastoma malignancy. Here we identify neuroblastoma-suppressive functions the p19-INK4d CDK inhibitor and uncover mechanisms its repression in high-risk neuroblastomas. Reduced expression was associated with poor event-free overall survival risk factors including amplified MYCN set 478 primary High repressed mRNA protein levels different models conditional expression....
The TP53 tumor suppressor pathway is abrogated by mutations in the majority of human cancers. Increased levels wild-type aggressive neuroblastomas appear paradox but are tolerated cells due to co-activation ubiquitin ligase, MDM2. role MDM2 antagonist, p14(ARF), controlling TP53-MDM2 balance neuroblastoma unresolved. In present study, we show that conditional p14(ARF) expression substantially suppresses viability, clonogenicity and anchorage-independent growth p14(ARF)-deficient or...
Neuroblastoma is the most common extracranial solid tumor in early childhood arising from precursor cells of neural crest. During last two decades advances have been made predicting outcome patient and improving therapeutic options [5]. However, high-risk neuroblastoma patients still a 5-year-survival rate less than 35% [2, 3, 7]. This due to drug resistance primary tumors or metastases after relapse. One important criterion classification amplified MYCN oncogene that crucial prognostic...
MYCN and HDAC2 jointly repress the transcription of tumor suppressive miR-183 in neuroblastoma. Enforced expression induces neuroblastoma cell death inhibits xenograft growth mice. Here we aimed to focus more closely on signaling network using a label-free mass spectrometric approach. Analysis cells transfected with either control or vectors identified 85 differentially expressed proteins. All six members minichromosome maintenance (MCM) complex, which is indispensable for initiation...
The migrational propensity of neuroblastoma is affected by cell identity, but the mechanisms behind divergence remain unknown. Using RNAi and time-lapse imaging, we show that ADRN-type NB cells exhibit RAC1- kalirin-dependent nucleokinetic (NUC) migration relies on several integral components neuronal migration. Inhibition NUC RAC1 kalirin-GEF1 inhibitors occurs without hampering proliferation ADRN identity. three clinically relevant expression dichotomies, reveal most up-regulated mRNAs in...
Abstract Aberrant expression of MYC family members predicts poor clinical outcome in many human cancers. Oncogenic profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that induces massive lipid peroxidation upon depletion cysteine, the rate-limiting amino acid for glutathione biosynthesis sensitizes cells ferroptosis, oxidative, non-apoptotic irondependent type cell death. In MYCN -amplified childhood neuroblastoma, resistance ferroptosis...
Abstract Signalling pathways exert finely tuned control over cell fate decisions that ultimately determine the behaviour of cancer cells. It could therefore be expected dynamics key pathway activation may contain prognostically relevant information and above which is contained in static nature traditional biomarkers. To investigate this hypothesis we have characterised network architecture regulating JNK stress signalling neuroblastoma cells applied an experimentally calibrated validated...
Introduction: MYCN and HDAC2 jointly repress the transcription of tumor suppressive miR-183 in neuroblastoma. Enforced expression induces neuroblastoma cell death inhibits xenograft growth mice.
<div>Abstract<p>The broad clinical spectrum of neuroblastoma ranges from spontaneous regression to rapid progression despite intensive multimodal therapy. This diversity is not fully explained by known genetic aberrations, suggesting the possibility epigenetic involvement in pathogenesis. In pursuit this hypothesis, we took an integrative approach analyze methylomes, transcriptomes, and copy number variations 105 cases neuroblastoma, complemented primary tumor- cell line–derived...
<div>Abstract<p>The broad clinical spectrum of neuroblastoma ranges from spontaneous regression to rapid progression despite intensive multimodal therapy. This diversity is not fully explained by known genetic aberrations, suggesting the possibility epigenetic involvement in pathogenesis. In pursuit this hypothesis, we took an integrative approach analyze methylomes, transcriptomes, and copy number variations 105 cases neuroblastoma, complemented primary tumor- cell line–derived...
<p>Description of additional methods and procedures used in the study. Also includes Supplementary References.</p>
<p>Genes whose hypermethylation and downregulation are associated with high-risk disease (HyperDownHR) de-repressed upon combination treatment epigenetically active drugs</p>
<p>Gene Ontology (GO) terms significantly enriched among genes whose hypermethylation and downregulation are associated with high-risk disease (HyperDownHR).</p>
<p>Neuroblastoma-specific mutations in genes whose hypermethylation and downregulation are associated with high-risk neuroblastoma disease (HyperDownHR)</p>