Targeting developmental vulnerabilities in childhood sarcomas

Childhood sarcomas are an aggressive and diverse group of mesenchymal-origin malignancies that collectively account for over a third of paediatric solid tumours. There has been little progress made in the treatment of childhood sarcomas in recent decades, and survival outcomes are poor compared to most other common paediatric cancers. Furthermore, long-term survivors of childhood sarcomas face disproportionately high morbidity from treatment. A unique feature of paediatric and adolescent sarcomas, compared to adult-type sarcomas, is that they arise from developing tissues and often share features with tissue-specific progenitors suggesting that they originate from cells that are arrested in a primitive developmental window. The developmental origins of paediatric sarcomas are also reflected in the incidence of different sarcoma types which correlate with age-specific tissue expansion and growth. In this review, we discuss the molecular mechanisms underpinning paediatric sarcomagenesis, focusing on how distortion of normal developmental programming, such as epigenetic regulation, embryonic signalling pathways, and aberrant growth pathways, contributes to childhood sarcoma development and progression. Finally, we will review the new and emerging therapeutic strategies seeking to target these developmental vulnerabilities.