ASSET · ASSET: Analysing and Striking the Sensitivities of Embryonal Tumours

Cancer is hallmarked by multiple genetic aberrations that lead to a functional derangement of cellular signalling networks. Embryonal tumours (ETs) comprising neuroblastoma, medulloblastoma and Ewing sarcoma, occur early in life, and thus may reveal pathogenetically relevant lesions clearer than adulthood tumours which carry passenger mutations accumulated during life. ASSET will exploit this fact by focussing on unravelling the signalling networks and their alterations in ETs. The basic hypothesis is that ETs share common pathogenetic principles that can be captured and made accessible to rational analysis by combining high-throughput and high content analysis of the genome, transcriptome and proteome with mathematical modelling. ASSET builds on a previous FP6 consortium, the European Embryonal Tumour Pipeline (EEPT), which generated high-throughput genomic and transcriptomic data on ETs. ASSET is the next logical step to add crucial functional information that will allow us to generate (i) defined in vitro and in vivo tumour systems; (ii) combined analysis of genomic mutations, transcriptome, miRNA expression and dynamic proteome changes; (iii) systematic perturbations; (iv) mathematical modelling to elucidate pathogenetic networks and their emergent behaviour; (v) the virtuous cycle of model validation in relevant biological model systems and clinical samples towards a major goal. This goal is to identify mechanistically understood network vulnerabilities that can be exploited for new approaches to the diagnosis and treatment of major paediatric tumours. Elucidating such core mechanisms will (i) improve understanding of and therapeutic options for these devastating childhood malignancies and (ii) enable a rational approach to deal with the complexity of the pathogenesis of adulthood cancers.