Childhood Cancers May Not Always Need Extra Mutations to Spread, Study Suggests

Data from a new study from scientists at the University of East Anglia and Liverpool John Moores University could help explain why some childhood tumors spread aggressively despite having relatively few genetic mutations. The findings, which are published in a new Trends Open review paper, indicate that childhood cancers may not always need to develop extra mutations to spread. Some cells may be able to switch into different cellular states between behaviors that help them grow, survive treatment, and ultimately spread. 

Furthermore, in the paper, titled “Developmental plasticity as a framework for paediatric cancer metastasis,” the scientists write that the process may be reversible. “Many childhood cancers arise from cells that are still closely linked to developmental programs used during early life,” and these programs “normally allow cells to move around the developing body, adapt to changing environments, and become different tissue types,”  said Darrell Green, PhD, an assistant professor and scientific group leader for RNA research at Norwich Medical School at University of East Anglia and one of the authors on the paper. “We think that cancer cells in children may exploit this natural flexibility of young, developing cells in order to spread.” 

To reach their conclusions, the scientists reviewed evidence from various childhood cancers, including neuroblastoma, Ewing sarcoma, osteosarcoma, medulloblastoma, and rhabdomyosarcoma. According to the paper, they integrated “genomic, epigenomic, developmental and single-cell evidence to examine how oncogenic lesions and developmental origins define accessible cellular states, while epigenetic, metabolic, and microenvironmental signals regulate transitions between them.”

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

This suggests that “rather than needing to acquire new mutations before they can spread, childhood cancer cells may already possess the ability to become metastatic,” Green explained. “The new, key question is not just what mutations they carry, but which cellular state they are in at a particular moment.” It is a point that “challenges the long-held assumption that cancers must acquire new mutations before they can metastasize.” 

The scientists hope that their work could ultimately lead to new types of treatments or at least point to ways to modify existing treatments. This means, for example, that 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. In fact, “it may eventually become possible to predict when cancers are preparing to spread,” Green said. 

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