Researchers from the Princess Máxima Center, the Netherlands Cancer Institute, and Oncode Institute have unearthed valuable knowledge about the origin of rhabdoid tumors, an aggressive form of cancer diagnosed in children, through studying mini, lab-grown tumors. Their research has managed to identify a potential target for future therapies.
Utrecht, Netherlands – Every year, five to ten children in the Netherlands are diagnosed with malignant rhabdoid tumor (MRT) at a very young age. These children often already have metastases at the time of their diagnosis. The tumor usually develops and grows during pregnancy, during the embryonic development of the child. Tumors can occur in various parts of the body, including the brain, kidneys, and in the soft tissue. Chemotherapy rarely leads to a cure, which means that the prognosis is often bleak. Further research into the origin of these tumors as well as the development of better, more targeted therapies is crucial.
Epigenetic research
The tumor develops as a result of the inactivation of the SMARCB1 gene, but other factors seem to play a role in this process as well. Irene Paassen, a PhD candidate at the Princess Máxima Center and Oncode Institute, explains: “When the SMARCB1 gene is inactive, we observed specific epigenetic differences between tumors of various children. These are changes that do not affect the DNA itself but do affect how the DNA is read. This activates another gene that is involved in cell division, the MYC gene, which should be turned off. Activating the MYC gene is crucial for tumor growth. The ability to reverse this activation provides new opportunities for the development of new therapies.”
Organoids
Paassen and her colleagues grew mini-tumors called organoids for this study. The tissue had been derived from tumor tissue from children treated at the Princess Máxima Center. The organoids closely mimic the way these tumors develop in children, providing an opportunity to investigate the effects of the (in)activity of the SMARCB1 gene by turning it on or off in tumor cells. This allowed researchers to study the underlying processes, which may lead to new targets for therapies.
This research generates large datasets that can be analyzed with advanced computer software. Paassen: “Our colleagues at the NKI are experienced in handling the kinds of measurements and data analyses required in our study to map out the way the DNA is folded. We needed these techniques to identify the key switches. The different areas of expertise complemented each other wonderfully in this study.”
“One of the crucial steps in our research was understanding how the DNA is folded in the nucleus,” says Ningqing Liu, former postdoctoral researcher at the NKI, and current assistant professor at Erasmus University. “All our cells contain 2 meters worth of DNA, which has to be folded up to fit inside a cell nucleus that has a diameter with the same width as one-tenth of a human hair. The way it is folded up, affects which parts of the DNA are activated, as in the case of the vital MYC gene.”
Next steps
The study was led by Princess Máxima Center and Oncode researcher Jarno Drost, together with Elzo de Wit, group leader at the NKI. The results, published in Nature Communications, offer new perspectives for future research. Drost: “We have been examining a rhabdoid tumor subtype that develops outside the brain, and are now looking for new that also apply to the variety that grows in the brain. We hope to find similarities that help us get an even more complete picture of the origin of this type of cancer. Further research into promising therapies may bring us closer to effective treatments for children with this aggressive cancer.” De Wit adds “We primarily conduct fundamental research into biological processes. It is great to see that our research into the way DNA is folded can contribute to a greater understanding of the processes that lead to the development of this aggressive type of cancer diagnosed in children.”
Contact
Esmeralda Schemmekes
Netherlands Cancer Institute
[email protected]
Cell: 628574972