© 2007
Freund/OncoLab
The group
Research in our group aims to identify molecular mechanisms involved in the biology of neuroblastoma, a childhood cancer with heterogeneous clinical courses, such as spontaneous regression in one subtype and malignant progression in another. In particular, we focus on the elucidation of MYCN oncogene functions in NB tumour initiation, progression and spontaneous regression. A comprehensive characterisation of the neuroblastoma trancriptome is an important prerequisite to systematically address these scientific questions.
Our role in EET-Pipeline
Construction and evaluation of a custom-made
neuroblastoma oligonucleotide-microarray (»neuroblastoma chip«):
A wide range of diagnostic procedures are available to characterise NB.
The prognostic predictive value is, however, uncertain, as shown by the
heterogeneous treatment outcome even within the same defined risk
groups. To develop a robust risk stratification tool based on gene
expression data, all key genetic determinants dictating NB phenotypes
should be adequately represented on such a diagnostic tool. We have
gathered gene expression data from a large set of NB tumours using
different high-throughput gene expression analysis tools (In
collaboration with our clinical partner at the University in Cologne):
standard expression arrays, customised arrays based on subtractive cDNA
libraries and SAGE libraries were used to define a comprehensive list of
genes reflecting the expression repertoire of individual NB phenotypes.
In addition, transcripts mapping to frequently altered chromosomal
regions were included. Based on this unique compilation of NB
phenotype-specific transcripts, we designed a customised microarray
consisting of 10,163 oligos representing 8,155 Unigene clusters and more
than 2,000 newly designed probes for transcripts that were not covered
by current “whole-genome” arrays.
To evaluate the prognostic value of the neuroblastoma chip, 502
expression profiles were generated retrospectively from 251 primary
tumours. For identification of a predictive gene signature, a PAM
algorithm was applied to a first set of 77 tumours from patients with
maximally divergent clinical outcome. The predictive power of the
resulting 144 gene PAM classifier was evaluated in a second set of 174
patients. We could demonstrate that classification errors made by the
currently used classification systems would have been corrected by a
gene expression based-classification system. Improvement of predictive
accuracy was observed in all NB risk groups. Thus, NB patients may
largely benefit from a gene expression-based classification system as
therapeutic intensity ranging from a wait-and-see approach to
multimodality therapy can be tailored to the individual risk of the
patient. To further evaluate our gene expression-based risk
stratification tool, all newly diagnosed patients enrolled in the German
Neuroblastoma Trial 2004 are being prospectively analysed. To our
knowledge, this is the first time that a gene expression-based
classification system is incorporated into a nationwide clinical cancer
trial.
MYCN and MYC-regulated stem cell markers as
therapeutic targets in neuroblastoma
Specific
pathways that control crucial steps during embryonic development are
often inappropriately reactivated during tumorigenesis. In addition
cancer cells seem to take advantage of cellular principles inherent to
normal stem cells, particularly the abilities to self-renew and
differentiate into multiple cell types. Cancer stem cells (tumour-initiating
cells) are believed to persist in tumours as a distinct population that
likely causes disease relapse. Members of the MYC transcription factor
family, in particular MYC and MYCN, are among very few genes that have
the ability to restore stem cell potential in differentiated cells.
Thus, deregulated MYC or MYCN protein functions may confer stem cell
potential to cancer cells, trigger relentless tumour growth and the high
rate of tumour relapse. However, the target genes and the molecular
mechanisms by which deregulated MYC proteins mediate these functions are
still elusive. We are using inducible overexpression and knockdown in
vitro systems that allow the regulation of MYCN and MYC functions in NB
cells. Selective knockdown of MYCN/MYC target genes is currently
performed to functionally dissect the MYCN/MYC pathway in NB cells.
Staff Member
Top 5 publications
1. Wei, J.S. *, B.T. Greer*, Westermann*, F S.M. Steinberg, C.-G. Son, Q.-R. Chen, C. Whiteford, S. Bilke, A.L. Krasnoselsky, N. Cenacchi, D. Catchpoole, F. Berthold, M. Schwab, and J. Khan, Prediction of clinical outcome using gene expression profiling and artificial neural networks for patients with neuroblastoma. Cancer Res, 2004. 64(19): p. 6883-91, *equal contribution
2. Henrich KO, Fischer M, Mertens D, Benner A, Wiedemeyer R, Brors B, Oberthuer A, Berthold F, Wei JS, Khan J, Schwab M, Westermann F. Reduced expression of CAMTA1 correlates with adverse outcome in neuroblastoma patients. Clin Cancer Res. 2006 Jan 1;12(1):131-8.
3. Oberthuer A, Berthold F, Warnat P, Hero B, Kahlert Y, Spitz R, Ernestus K, Konig R, Haas S, Eils R, Schwab M, Brors B*, Westermann F*, Fischer M*. Customized oligonucleotide microarray gene expression-based classification of neuroblastoma patients outperforms current clinical risk stratification. J Clin Oncol. 2006 Nov 1;24(31):5070-8. *equal contribution
4. Westermann F., Kai-Oliver Henrich, Jun S. Wei, Werner Lutz, Matthias Fischer, Rainer König, Ruprecht Wiedemeyer, Volker Ehemann, Benedikt Brors, Axel Benner, Javed Khan and Manfred Schwab. High Skp2 expression characterizes high-risk neuroblastomas independent of MYCN status. Clin Cancer Res. 2007; 13 (16): 4695-703.
5. Sawinska M. Schmitt J.G., Sagulenko E., Westermann F., Schwab M., Savelyeva L. Novel aphidicolin-inducible common fragile stie FRA9G maps to 9p22.2, within the C9orf39gene. Gene Chromosomes Cancer. 2007 Nov; 46(11): 991-9.