Division of Neuroblastoma Genomics

PD Dr. Frank Westermann

Figure 1: Clustering based on enhancer activity as defined by tumor-ChiP-seq.
Figure 2: Translocation event in neuroblastoma cells analyzed using 4C– enhancer hijacking.
© dkfz.de

Neuroblastoma is the most common pediatric single-entity solid cancer derived from primitive cells of the peripheral sympathetic nervous system. It is characterized by heterogeneous clinical phenotypes ranging from spontaneous regression to malignant progression despite intensive multimodal therapies. Malfunction of the MYCN transcription factor is a key feature of neuroblastoma biology and is involved in almost every aspect of tumor formation such as unrestricted proliferation, differentiation inhibition, reprogramming of cellular energetics, angiogenesis, infiltration/metastasis and genomic instability.

Overall aim of our work is to integrate next-generation molecular diagnostics for a more precise patient risk stratification and to develop molecularly targeted therapies based on a better understanding of the molecular mechanisms underlying neuroblastoma tumorigenesis. We use microarray-based technologies as well as next-generation sequencing with the specific aim to define genetic and epigenetic alterations associated with distinct neuroblastoma subtypes (project NB genome/epigenome/transcriptome). The project NB oncogenes activated by enhancer hijacking focuses on the comprehensive characterization of enhancer translocations in NB using an integrated analysis combining whole genome sequencing (WGS), RNA-seq, ChIP-seq and 4C chromatin context analyses. In addition, we use high-throughput si/shRNA screens to disclose neuroblastoma-specific vulnerabilities associated with distinct genetic aberrations, such as amplified MYCN, TERT rearrangements, or ATRX deletions (project NB Achilles). These structural and functional genomic screens are further complemented by systems biology approaches to understand MYCN protein functions regulating cell cycle progression, apoptosis and senescence in normal and cancer cells (project MYC-NET). Finally, we have a focus on the identification of molecular pathways involved in the activation of chromosomal fragile sites as a prominent initiating event in the generation of chromosomal damage, particularly DNA deletions and DNA amplifications (Fragilome Project).

NB super-enhancer visualization tool
NB developmental programs visualization tool

Contact

PD Dr. Frank Westermann
Neuroblastoma Genomics (B087)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
69120 Heidelberg
Tel: +49 6221 423219

Selected Publications

  • Jansky, S., A. K. Sharma, V. Körber, A. Quintero, U. H. Toprak, E. M. Wecht, M. Gartlgruber, A. Greco, E. Chomsky, T. G. P. Grünewald, K.-O. Henrich, A. Tanay, C. Herrmann, T. Höfer and F. Westermann (2021). "Single-cell transcriptomic analyses provide insights into the developmental origins of neuroblastoma." Nature Genetics.
  • Hartlieb, S. A.*, L. Sieverling*, M. Nadler-Holly, M. Ziehm, U. H. Toprak, C. Herrmann, N. Ishaque, K. Okonechnikov, M. Gartlgruber, Y.-G. Park, E. M. Wecht, L. Savelyeva, K.-O. Henrich, C. Rosswog, M. Fischer, B. Hero, D. T. W. Jones, E. Pfaff, O. Witt, S. M. Pfister, R. Volckmann, J. Koster, K. Kiesel, K. Rippe, S. Taschner-Mandl, P. Ambros, B. Brors, M. Selbach, L. Feuerbach and F. Westermann§ (2021). "Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome." Nature Communications 12(1): 1269.
  • Gartlgruber, M., A. K. Sharma, A. Quintero, D. Dreidax, S. Jansky, Y.-G. Park, S. Kreth, J. Meder, D. Doncevic, P. Saary, U. H. Toprak, N. Ishaque, E. Afanasyeva, E. Wecht, J. Koster, R. Versteeg, T. G. P. Grünewald, D. T. W. Jones, S. M. Pfister, K.-O. Henrich, J. van Nes, C. Herrmann*§ and F. Westermann*§ (2021). "Super enhancers define regulatory subtypes and cell identity in neuroblastoma." Nature Cancer 2(1): 114-128. *equal contribution
  • Jones, D. T. W., A. Banito, T. G. P. Grunewald, M. Haber, N. Jager, M. Kool, T. Milde, J. J. Molenaar, A. Nabbi, T. J. Pugh, G. Schleiermacher, M. A. Smith, F. Westermann and S. M. Pfister (2019). "Molecular characteristics and therapeutic vulnerabilities across paediatric solid tumours." Nat Rev Cancer 19(8): 420-438.
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