Marc Zuckermann
A5054614170- Glioma Diagnosis and Treatment
- CRISPR and Genetic Engineering
- RNA modifications and cancer
- Cancer-related molecular mechanisms research
- Single-cell and spatial transcriptomics
- Cancer, Hypoxia, and Metabolism
- Virus-based gene therapy research
- Pluripotent Stem Cells Research
- Cancer Research and Treatments
- Hereditary Neurological Disorders
- RNA Research and Splicing
- Chromatin Remodeling and Cancer
- Cancer Mechanisms and Therapy
- Neuroblastoma Research and Treatments
- Advanced biosensing and bioanalysis techniques
- Ubiquitin and proteasome pathways
- Neurofibromatosis and Schwannoma Cases
- Low-power high-performance VLSI design
- Cell Image Analysis Techniques
- Hedgehog Signaling Pathway Studies
- RNA Interference and Gene Delivery
- Cancer Cells and Metastasis
- ATP Synthase and ATPases Research
- Congenital Ear and Nasal Anomalies
- Cytokine Signaling Pathways and Interactions
German Cancer Research Center
2015-2024
Heidelberg University
2015-2024
Hopp Children's Cancer Center Heidelberg
2020-2024
University Hospital Heidelberg
2022-2024
National Center for Tumor Diseases
2024
Deutschen Konsortium für Translationale Krebsforschung
2021-2023
DKFZ-ZMBH Alliance
2023
Jilin University
2013
First Hospital of Jilin University
2013
University of Portsmouth
2013
Abstract In vivo functional investigation of oncogenes using somatic gene transfer has been successfully exploited to validate their role in tumorigenesis. For tumour suppressor genes this proven more challenging due technical aspects. To provide a flexible and effective method for investigating loss-of-function alterations influence on tumorigenesis, we have established CRISPR/Cas9-mediated disruption, allowing targeting TSGs. Here demonstrate the utility approach by deleting single ( Ptch1...
Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years age, and carried out histologic review, methylation profiling, custom panel, genome, or exome sequencing. After excluding tumors representing other established entities subgroups, we identified 130 to be part an "intrinsic" spectrum disease specific infant...
Mutations in chromatin modifier genes are frequently associated with neurodevelopmental diseases. We herein demonstrate that the chromodomain helicase DNA-binding protein 7 (Chd7), CHARGE syndrome, is indispensable for normal cerebellar development. Genetic inactivation of Chd7 granule neuron progenitors leads to hypoplasia mice, due impairment differentiation, induction apoptosis and abnormal localization Purkinje cells, which closely recapitulates known clinical features cerebella...
Abstract YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions sufficient to drive malignant transformation mice, and resulting tumors share histo-molecular characteristics human ependymomas. Nuclear localization protein is mediated by MAMLD1 independent YAP1-Ser127 phosphorylation. Chromatin immunoprecipitation-sequencing analyses YAP1-MAMLD1-positive ependymoma reveal...
Abstract Background Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses adult patients mitogen-activated protein kinase (MAPK)-driven solid tumors. Methods We investigated antitumoral activity of monotherapy as well combination MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy pLGG. Patient-derived pLGG models...
Abstract Background Distinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic targets. Previous strategies to map cell-of-origin typically involved comparing human murine embryonal tissues, which potentially limited due species-specific differences. The aim this study was unravel 3 most common pediatric tumors, ependymoma, pilocytic astrocytoma, medulloblastoma, using a developing...
One key advantage of the CRISPR/Cas9 system in comparison with other gene editing approaches lies its potential for multiplexing. Here, we describe an elaborate procedure that allows assembly multiple gRNA expression cassettes into a vector choice within single step, termed ASAP(Adaptable System Assembly multiplexed Plasmids)-cloning. We demonstrate utility ASAP-cloning CRISPR-mediated applications, including efficient multiplex editing, robust transcription activation and convenient...
Abstract Background Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating MET receptor tyrosine kinase often occur infant-type hemispheric (IHG) but also other pHGG are associated with devastating morbidity mortality. Methods To identify new treatment options, we established characterized two novel orthotopic mouse models harboring distinct fusions. These included an...
Abstract Recent advances allowing the genomic analysis of individual cells from a bulk population have provided intriguing new insights into areas such as developmental processes and tumor heterogeneity. Most approaches to date, however, rely on availability fresh surgical specimens, thereby dramatically reducing ability profile particularly rare tissue types. Pediatric central nervous system tumors – leading cause childhood cancer deaths represent one example, where often only frozen rather...
Abstract Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized deficits sensory and autonomic neurons, neuronal defects central nervous system have been described. ELP1 highly expressed normal developing adult cerebellum, but its role cerebellum development unknown. To investigate cerebellar function of Elp1, we knocked out Elp1 granule cell progenitors (GCPs)...
Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized deficits sensory and autonomic neurons, neuronal defects central nervous system have also been described. Although ELP1 expression remains high normal developing adult cerebellum, its role cerebellar development unknown. To explore of Elp1 we knocked out granule cell progenitors (GCPs) examined outcome on...
Understanding the cellular origins of childhood brain tumors is key for discovering novel tumor-specific therapeutic targets. Previous strategies mapping typically involved comparing human to murine embryonal tissues 1,2 , a potentially imperfect approach due spatio-temporal gene expression differences between species 3 . Here we use an unprecedented single-nucleus atlas developing cerebellum (Sepp, Leiss, et al) and extensive bulk single-cell transcriptome tumor data map their with focus on...
Abstract Oncogenic fusion events involving c-MET have been observed in up to 12% of pediatric high-grade glioma (pHGG). MET inhibitors displayed potent initial responses rearranged tumors but acquired resistance single agent modalities invariably occurs. To identify new treatment options against these tumors, we established two novel orthotopic mouse models including an immunocompetent, murine allograft and intracranial patient-derived xenograft (PDX), both harboring distinct fusions. We...
Abstract Modeling cancer in mice through engineering of candidate genes the germline has long been gold standard for validation putative oncogenes or tumor suppressor (TSGs). For TSGs, whereby loss-of-function (LOF) mutations act as a driver malignant transformation, this traditionally accomplished using constitutive cell type-specific knockout strategies mediated by homologous recombination embryonic stem cells. While allows evaluation susceptibility to generation genetically engineered...
EPN-30. YAP1-MAMLD1 FUSIONS ALONE ARE SUFFICIENT TO FORM SUPRATENTORIAL EPENDYMOMA-LIKE TUMORS IN MICE Kristian W. Pajtler1,2, Sebastian Brabetz1, Monika Mauermann1, Norman Mack1, Laura Sieber1, David T. Jones1, Hendrik Witt1,2, Huiqin Korkel-Qu3, Marc Zuckermann4, Jan Gronych4, Andrey Korshunov5,6, Capper5,6, Hai-Kun Liu3, Stefan M. Pfister1,2, Marcel Kool1, and Daisuke Kawauchi1; German Cancer Research Center, Division of Pediatric Neurooncology, Heidelberg, Germany; University Hospital...
<p>Supplementary Figures and Legends</p>
<div>Abstract<p>Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years age, and carried out histologic review, methylation profiling, custom panel, genome, or exome sequencing. After excluding tumors representing other established entities subgroups, we identified 130 to be part an “intrinsic” spectrum...