Community Research and Development Information Service - CORDIS


RealLifeCancer Report Summary

Project ID: 340735
Funded under: FP7-IDEAS-ERC
Country: Netherlands

Mid-Term Report Summary - REALLIFECANCER (Challenging the gaps in global cancer concepts by a real life tumor: human childhood neuroblastoma)

Neuroblastoma is an aggressive paediatric tumour. High stage neuroblastoma typically go in complete remission upon therapy, but very often relapse as therapy-resistant tumour. Neuroblastoma is marked by a paucity of gene defects, but in contrast has frequent gains and losses of large chromosomal regions. Immediate questions are therefore the genetic causes of neuroblastoma and the mechanisms how tumours relapse as therapy-resistant disease.
In this project we have identified from our whole genome sequence data and super-enhancer analyses that chromosomal rearrangements placing super-enhancers upstream of TERT are frequent in neuroblastoma (Valentijn et al., Nature Genetics 2015). In addition, mutations in the RAS-MAPK signalling pathway were associated with the occurrence of relapses (Eleveld et al., Nature Genetics 2015). In addition, we established that neuroblastoma tumours consist of two different tumour cells types. They share the same genetic defects, but display divergent phenotypes probably resembling normal developmental stages of the adrenergic differentiation lineage. The two cell types strongly differ in gene expression profiles as well as in super-enhancer patterns. This allowed us to identify the genes that are associated to cell-type specific super enhancers. For each cell type, we thus identified a core set of about 15 super-enhancer-associated transcription factors. They are highly expressed and may form a feed-forward network imposing cell identity to each of the tumour cell types. Activation of one of these transcription factors indeed could induce a switch between the two cell types, including reformatting of the super-enhancers and the expression profiles. Since the more primitive one of the two cell types was found to be resistant to chemotherapeutics in vitro, and accumulated in post-therapy tumours and relapses in vivo, the two cell types might be clinically important and mediate development of therapy resistant relapses. The super enhancer-associated TF networks, probably meant for lineage control in normal development, thus could impose two cellular states of neuroblastoma that shape intra-tumour heterogeneity.

Reported by

Academisch Medisch Centrum bij de Universiteit van Amsterdam
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