Epigenetic researchAn MRT results from the deactivation of the SMARCB1 gene. However, more factors seem to play a role. In fact, previous research from the Drost group shows that healthy cells can also have SMARCB1 gene deactivation but do not turn into tumor cells.
Irene Paassen, PhD candidate in the Drost group at the Máxima Center and Oncode Institute: 'When the SMARCB1 gene is inactive, we saw specific so-called epigenetic changes between tumors of different children. These are changes that do not affect the DNA itself, but do affect the way the DNA is read. As a result, another gene involved in cell division, the MYC gene, is 'turned on' when it should be off. Turning on the MYC gene is crucial for tumor growth. The possibility of reversing this offers opportunities for the development of new therapies.'
Together with co-first authors Dr. Ningqing Liu, former postdoctoral researcher at the NKI and now assistant professor at Erasmus University, and Dr. Lars Custers, former PhD student in the Drost group, Paassen published the findings today in the scientific journal Nature Communications.
OrganoidsFor this study, Paassen and her colleagues cultured MRT organoids. For this they used tumor tissue from children treated at the Máxima Center. Paassen: 'The growth of the organoids corresponds very well to how these tumors develop in the child. We can thus investigate the effect of the presence or absence of the SMARCB1 gene by turning the gene back on in the tumor cells. It allows us to study the underlying processes and possibly find new targets for therapies.
Next, Paassen and Liu examined the properties of the organoids and the effect of turning the SMARCB1 gene back on. For example, they looked at changes in the behavior of the tumor cells. They saw that turning SMARCB1 back on made the cells stop growing. And that a similar process could possibly be achieved with the help of a drug. Paassen: 'Our fellow researchers at the NKI have a lot of experience with the type of measurements and data analyses that were needed for this study to map the ways in which DNA is folded. We needed those techniques to then identify the important switches. So we complemented each other very nicely in this research with different areas of expertise.'
Dr. Liu: 'One of the crucial steps in this research was understanding how DNA is folded in the nucleus. All our cells contain 2 meters of DNA and this has to be folded into a cell nucleus that has a cross-sectional area about the thickness of a tenth of a human hair. This folding affects which parts of the DNA are turned on, such as in our case the important MYC gene.' This research generated large data sets that were analyzed with sophisticated computer software.
Next stepsResearch group leader at the Máxima Center and Oncode researcher Dr. Jarno Drost led the study together with Dr. Elzo de Wit, research group leader at the NKI. De Wit: 'We mainly do basic research into biological processes. It is nice to see that our fundamental research into the folding of DNA can contribute to a better understanding of the processes that lead to this aggressive form of childhood cancer.'
Drost sees opportunities for further research as a result of these results. 'In this study, we examined the subtype of rhabdoid tumors that arise outside the brain. We are currently looking to see if the same processes are involved in the development of the brain variant. We hope to find similarities that will help us get an even more complete picture of the origin of this type of cancer. In addition, I want to do further research on the therapy of which we now saw a positive effect in these mini-tumors grown in the lab. This will hopefully bring us another step closer to finding new targeted therapies for children with this aggressive form of cancer.'
This research was made possible in part thanks to funding from the European Research Council (ERC), KiKa/Maarten van der Weijden foundation, the Netherlands Organization for Scientific Research (NWO) and Nikai 4 Life.