Ref ID: 323.1

The Delta-Notch pathway integrates the wnt pathway, the noradrenalin synthesis route and the neurotrophin pathway in neuroblastoma

Vera van Limpt1, Alexander Schramm2, Alvin Chan1, Angelika Eggert2, Rogier Versteeg1

Department of Human Genetics, Academic Medical Center, University of Amsterdam, The Netherlands; Dept. of Hematology/Oncology, University Children's Hospital of Essen, Germany.

The Delta-Notch pathway plays an important role in embryonal development in species ranging from Drosophila to humans. It controls cell fate decisions during differentiation of cell lineages. The Dlk-1 gene is very highly expressed in normal adrenal medulla and in a subset of neuroblastoma cell lines. The expression in cell lines closely correlates with expression of Dopamine Beta Hydroxylase (DBH), one of the key enzymes in the noradrenalin synthesis route. Neuroblastomas with high Dlk-1 expression therefore probably represent tumors from a relatively late differentiation stage of the chromaffin cell lineage. In general, Notch genes function as receptors for Delta proteins on adjacent cells and this interaction can start a process of divergent differentiation between the two cells. Indeed, the Notch3 gene shows an inverse expression pattern with Dlk-1 in the neuroblastoma cell line panel. Notch3 positive cells therefore represent another differentiation stage or lineage than Dlk1 positive cells. The Delta-Notch pathway includes many different genes. We used SAGE and micro-arrays to analyze the changes in gene expression in neuroblastoma cell lines transfected with members of the Delta-Notch pathway. This showed that Dlk1 can control the expression of genes of the Wnt pathway. In addition, we found that activation of neurotrophin receptors of the Trk family can strongly regulate expression of members of the Delta-Notch route in neuroblastoma. The final result of these interactions is de-differentiation of neuroblastoma cells and abrogation of Dopamine Beta Hydroxylase expression. This identifies the Delta-Notch pathway as a central player in differentiation route of the adreno-sympathetic cell lineage. We are sequencing the key genes in a large neuroblastoma tumor series to establish whether defects in the pathway contribute to neuroblastoma pathogenesis. 

Presentation mode(s): oral-presentation – pc-projector