New tools to better understand and fight paediatric sarcomas
Sarcomas are malignant tumours that develop in bone or connective tissue. They can occur in adults, but are more frequent in children and young adults. “There are many challenges to treating these types of tumours,” explains PedSarc project coordinator Ana Banito from the German Cancer Research Center. “For one thing, there are many different subtypes. What works for one subtype may not be suitable for another.” Each sarcoma subtype is also relatively rare, so the collection of sufficient patient samples and data has long been a challenge. As a result, scientists have found it difficult to fully understand the molecular pathways that promote sarcoma development. The PedSarc project, funded by the European Research Council, set out to address these shortcomings. “We had two main aims,” says Banito. “First, to understand how specific genetic alterations give rise to sarcoma. And second, to develop more flexible mouse models that will allow us to test specific biological hypotheses and therapeutic strategies.”
Specific genetic alterations identified
At the molecular level, the project used several tools – such as the gene editing tool CRISPR – to study gene regulation and gene inactivation. The project team was able to identify specific gene fusions that could play a role in the development of paediatric sarcomas. The project achieved a significant breakthrough with its work on a specific protein, SS18-SSX, which gives rise to synovial sarcoma, the second most common malignant soft tissue tumour in children and young adults. Banito and her team were able to identify the molecular mechanisms of protein-gene interaction that enables it to regulate specific genes to promote cancer. “The goal now is to find out how to disrupt this activity, by inhibiting this gene-protein interaction,” adds Banito.
Testing specific therapeutic strategies
The PedSarc project also focused on new developing methods for investigating sarcomas in vivo. For this, a new way of delivering transposon vectors into muscle tissue was pioneered in mice. These fragments of DNA mediate the insertion of specific mutated genes into the genome. By applying a small electric pulse, the team was able to insert these fragments to mimic gene fusion activation in normal cells, revealing if and how these fusions give rise to sarcomas. “The mouse model development in this project has been especially innovative,” says Banito. “It enables us to rapidly test several genetic alterations in mice with intact immune systems, and potentially use it as a model to test novel therapies including immunotherapies. We are currently preparing a paper describing these models, and will make this available as a resource for the scientific community.”
New tools to overcome sarcoma
Banito believes that the project’s two-step approach – of better understanding how genetic alterations give rise to sarcoma, and developing more flexible mouse models – has helped to shine a light on how sarcomas arise. The hope is that over the longer term, the project’s results will give rise to new treatments that can benefit patients. For synovial sarcoma, the project has already helped to identify a key molecular mechanism for new therapies to target. The new mouse models should also enable scientists to test many more therapeutic strategies, and answer more questions concerning sarcoma. “Our mouse models are already being used to test immunotherapies, and we plan to use them in subsequent studies to test additional therapeutic strategies,” notes Banito. “We are still a long way from finding treatments for all sarcoma subtypes, but now we have more tools to overcome this challenge.”
Keywords
PedSarc, paediatric, sarcoma, tumours, cancer, genes, protein, immunotherapies
