King's College London

Neuroblastoma typically affects young children, developing in the adrenal glands or nervous system. A major challenge in treating this disease is its complex genetic makeup. Neuroblastoma often involves changes in the number of copies of certain chromosomes (CNAs) - like having extra or missing pages in a cell's instruction manual. Another key factor is the MYCN oncogene, which normally helps cells develop but becomes overactive in neuroblastoma, driving uncontrolled cell proliferation. These genetic abnormalities are believed to be key drivers of the disease, contributing to its aggressive nature and unpredictable response to treatment.

The team, led by Dr Anestis Tsakiridis, University of Sheffield will focus on how these genetic changes disrupt the normal development of neural crest cells. Neural crest cells form various parts of the nervous system and other tissues where neuroblastoma originates from. By meticulously tracking the impact of CNAs and MYCN overactivation on these cells, the researchers hope to gain crucial insights into the cancer's origins and the factors that contribute to its heterogeneity (the presence of diverse cell types within a single tumor).

Dr Tsakiridis and his team will use human stem cells grown in a petri dish to produce “mutant” neural crest cells carrying the same genetic errors as those seen in neuroblastoma. This will allow them to study how these errors affect the cells as they grow and how they lead to cancer. 

Prof Karen Liu, a developmental biologist at King’s College London is part of the team working to understand genetic changes that affect cell movements leading to metastasis. They will also investigate how these genetically altered cells respond to standard chemotherapy agents, seeking to identify mechanisms of drug resistance and potential vulnerabilities that could be exploited by new therapies.

A key element of the project involves combining experimental data with computational modeling, work that will be led by Prof Alex Fletcher from the University of Sheffield. This approach will allow the researchers to simulate and predict how different combinations of genetic alterations contribute to tumor evolution and the emergence of resistant cell populations - a major obstacle in successful neuroblastoma treatment.

“By examining how the complex genetic code of neuroblastoma converts normal embryonic neural crest cells into their cancerous counterparts, we aim to identify new therapeutic targets for treatment - potentially leading to reduced drug resistances, preventing relapses and saving lives.”