What happens in cells to make neuroblastoma develop and how can we stop this?

Childhood cancers are responsible for around one quarter of deaths in children. However, we still don’t know how exactly they begin, or why. They normally start before birth, when some of the embryo’s normal cells get a genetic mutation and go rogue. When this happens, the cells reproduce and grow out of control, resulting in cancer. It is very important to understand how this process happens, in order to develop effective treatment for these cancers or to help prevent them.

One common feature of many children’s cancers, such as neuroblastoma, is that their cells gain a partial extra copy of one or more chromosomes. Almost all human cells have 46 chromosomes in them, which store all of a person’s genetic code. Within these DNA instructions are genes, which tell the cell how to behave and how to make proteins for vital functions. When cells gain extra copies of chromosomes there is normally a lot of MYCN, a tumour-promoting protein, in the cell. This happens frequently in neuroblastoma, which is a solid tumour that affects around 100 children per year in the UK. It is very difficult to cure when high-risk and its treatment is associated with serious long-term side-effects.

In this project, Dr Anestis Tsakiridis will be working in collaboration with Dr Helen Bryant from the University of Sheffield, who is a specialist in DNA damage. The researchers will examine how the extra bits of chromosome and MYCN work together to promote the ’conversion’ of normal early cells into cancer cells. To answer this question, Dr Tsakiridis’ team at the University of Sheffield will use human stem cells grown in a petri dish to produce the type of early cells that give rise to neuroblastoma.

In this model system they will examine how extra copies of chromosomal parts and MYCN cause cancer cells to happen. In particular, they plan to investigate whether having the extra bits of chromosome actually protects cells that are destined to become cancerous from damage to their DNA. DNA damage normally kills cells, so Dr Tsakiridis believes that the extra bits of chromosome might protect from DNA damage, allowing the cells to survive and become cancerous.

His team will also test whether the same thing happens during development of another aggressive childhood cancer that grows in the brain, called medulloblastoma. If their idea is correct, then drugs that prevent the DNA damage being repaired could be used to treat cancer. In the final part of the project, the researchers will test potential drugs in neuroblastoma cancer cells in the lab. Dr Tsakiridis hopes that this project will increase understanding of how these lethal cancers arise in children and lead to the development of new therapies.