Oncogenic aberration of development in embryonal tumors

Cancer remains one of the leading causes of death in children, despite great advances in treatment methods and although many important mutations are now known. Some tumors, which typically appear in early childhood, arise from mutations that occur in the developing fetus and then manifest shortly after birth. These so-called embryonal tumors include particularly devastating types of cancer such as neuroblastoma (NB) and nephroblastoma, which is also called Wilms tumor (WT). Common mutations in embryonal tumors affect genes that are important for the proper development of various tissues in the embryo. These are, for example, the sympathetic nervous system in NB or the kidneys in WT. We have observed that many mutations occur almost exclusively in tumors of one tissue type, although the affected genes are also active in other tissues. The OncoDev project will unravel the molecular basis for this intriguing disparity. We hypothesize that the effects of mutations and whether they lead to tumor formation are influenced not only by the activity of the affected genes, but also by the molecular state of the cells. This state is in turn influenced by many external and internal signals that the cells encounter during their development. The current state of a cell is reflected in its epigenetic structure, i.e. in biochemical changes that take place in addition to the cells` genetic code and that shape their cell identity. These biochemical changes can be effectively measured using modern genomics technologies. However, the use of these technologies is a destructive process that precludes direct application to humans. In this project, we will use human pluripotent stem cells to recreate relevant stages of embryonic development in the laboratory, which will provide us with a practical model system to study embryonic tumorigenesis in an ethical manner. To this end, we will work with experts in various stem cell technologies in the United Kingdom and Japan. We will then compare the results of our experiments with data from left-over tumor material from biopsies and surgeries donated for research purposes to demonstrate relevance to actual tumor biology. Taken together, our data will provide a mechanistic explanation for our epidemiological observations. This may help in the future to develop better treatment strategies to counteract tumor development.