Childhood cancer cells shape-shift to spread without genetic mutations

Researchers at the University of East Anglia (UK) have proposed an explanation for why some childhood tumors spread aggressively around the body despite having relatively few genetic faults. 

For years, experts believed cancers become more dangerous by accumulating genetic mutations that allow them to invade new tissues and evade treatment. 

But a new paper published today shows how childhood cancers may not always need extra mutations to spread. 

Instead, the authors say cancer cells may be able to "shape-shift" into different cellular states - switching between behaviors that help them grow, survive treatment and spread to other organs. 

Crucially, the authors say that the process may be reversible. And they hope that their work could one day lead to new types of treatment, or even modifying treatments already available. 

 Dr Darrell Green, from UEA's Norwich Medical School, said: "Metastasis, where cancer spreads from its original site to other parts of the body, is the leading cause of cancer-related deaths in children. 

But scientists have struggled to explain why some childhood cancers spread aggressively despite having relatively few genetic mutations, which is the apparently opposite biology to cancer in adults. 

Many childhood cancers arise from cells that are still closely linked to developmental programs used during early life. 

These programs normally allow cells to move around the developing body, adapt to changing environments and become different tissue types. 

We think that cancer cells in children may exploit this natural flexibility of young, developing cells in order to spread." 

Dr. Darrell Green, Lead Researcher, UEA's Norwich Medical School

How the research happened 

The team reviewed evidence from a wide range of childhood cancers, including neuroblastoma, Ewing sarcoma, osteosarcoma, medulloblastoma and rhabdomyosarcoma. 

They propose that genetic changes determine which cellular identities cancer cells can adopt, while reversible changes in gene activity dictate whether those cells become aggressive, resistant to treatment or capable of forming metastatic tumors. 

"Rather than needing to acquire new mutations before they can spread, childhood cancer cells may already possess the ability to become metastatic," said Dr Green. 

"The new, key question is not just what mutations they carry, but which cellular state they are in at a particular moment. 

"This challenges the long-held assumption that cancers must acquire new mutations before they can metastasise." 

Future therapies 

Instead of focusing solely on killing tumor cells or targeting mutated genes, future therapies might aim to stop cancer cells entering the states that make them dangerous in the first place. 

"It may eventually become possible to predict when cancers are preparing to spread," said Dr Green. 

"Emerging technologies, including single-cell analysis, monitoring of circulating tumor cells and advanced computer modelling, could help doctors track changes within tumors and identify periods when patients face the greatest metastatic risk," he added. 

The researchers stress that the work does not represent a new treatment and more research is needed. However, they believe understanding these cellular transitions could ultimately reveal new opportunities to prevent cancer spread before it begins. 

This research was led by UEA in collaboration with Liverpool John Moores University. 'Developmental plasticity as a framework for pediatric cancer metastasis' is published in the Cell Press journal Trends Open.