Atypical teratoid rhabdoid tumors (ATRTs) are rare but highly aggressive tumors of the central nervous system. They mainly occur in young children. In the Netherlands, a few children are diagnosed with this condition each year, often before their third birthday. The tumor typically arises due to the loss of the SMARCB1 gene, which normally acts as a crucial brake on cell growth.
There are three subtypes of ATRT, each with its own characteristics. However, there are currently no treatments specifically tailored to these subtypes. Therefore, the researchers aimed to understand better the cellular-level differences that lead to the development of the various forms.
Insight into tumor development
The research team, led by Prof. Dr. Jarno Drost and Prof. Dr. Marcel Kool, mapped which genes are active in each tumor cell and how accessible the DNA is. Drost and Kool are both research group leaders at Máxima. In addition, Drost is Oncode investigator and Kool is also appointed at KiTZ - Hopp Children's Cancer Center Heidelberg.
Jarno Drost explains: ‘We found that each ATRT subtype follows its own developmental pathway, resembling the way different brain cells emerge during early fetal development.’
Maturing tumors
Based on the different developmental pathways, the researchers cultured mini-tumors in the lab. They used tumor tissue from children who are or were being treated at the Máxima Center. In these models, they investigated whether they could steer the tumor cells toward a more mature and slower-dividing state.
This proved successful. By adding substances that stimulate the developmental pathway of a specific subtype, the cells began to behave more like ‘normal’ brain cells. They divided more slowly and thus became less aggressive.
‘We show that the development of ATRT cells can be influenced,’ says Marcel Kool. ‘This provides leads for new therapies that target the subtype and maturation status of the tumor.’
Next steps
The researchers hope their findings will ultimately lead to new treatments for children with ATRT. To take that step, further research is required.
The research, to which PhD candidate Jiayou He and former PhD candidate Dr. Irene Paassen (both from the Drost group) and PhD candidate Dr. Enrique Blanco Carmona from the Kool group in Heidelberg contributed as first authors, was published today in the journal Neuro-Oncology.
The research was made possible in part thanks to the collaboration between the Máxima Center and the Hopp-KiTZ pediatric oncology center in Heidelberg within the EU CAN KIDS alliance (European Alliance for a Childhood Without Cancer), the European Research Council, the Dutch Research Council (NWO), and the Children Cancer-Free Foundation (KiKa).