Versteeg R.: Regulatory networks in cancer

The research program focuses on the elucidation of the regulatory networks underlying pathogenesis of the childhood tumors neuroblastoma, medulloblastoma and rhabdomyosarcoma. Affymetrix profiling was performed on large series of these tumors. Genes with a role in these tumors are systematically switched on or switched off in cell lines by inducible cDNA or siRNA expression (Tet-on system). RNA from time-courses of these cell lines was analyzed by Affymetrix expression arrays, usually in triplo and of different clones. Downstream pathways of about 15 genes were analyzed in this way. Elaborate bioinformatics programs were generated to identify downstream networks of the manipulated genes and to relate these data to the expression patterns observed in the tumor series. As each of the manipulated genes (like MYCN, NOTCH, EZH2, MSX1, CDK2) appear to regulate expression of hundreds of downstream genes, the emerging networks appear to be complex. The networks are further analyzed by silencing of transcription factors and other key genes in the networks. This requires an increase in the number of gene manipulations. For this purpose we have started to silence gene expression by
lentivirally encoded siRNAs (TRC library). Over 15 genes were efficiently silenced this way and their downstream pathways are currently analyzed by microarrays.



Theme: Oncology