Photo: The photo shows neuroblastoma cells in which the oncogene MYCN is stained turquoise. Pink represents a chromatin change characteristic of dormant cells. The nuclei are highlighted in blue. It is clearly visible that cells with few copies of the MYCN gene are more likely to be in a dormant state. © Charité | Giulia Montuori (kindly supported by the Max Delbrück Center’s Advanced Light Microscopy technology platform)
Berlin, August 8, 2025
Neuroblastomas, which primarily affect children, are often difficult to treat. Researchers at the Charité – Universitätsmedizin Berlin and the Max Delbrück Center have discovered why this might be the case. In the journal Cancer Discovery*, they propose a new therapeutic approach that combats particularly resistant tumours.
Neuroblastoma can be a particularly insidious tumour. Although about half of them regress, sometimes even without treatment, the other half grows very quickly. These tumours often respond well to chemotherapy initially, but often recur after one to two years. A characteristic feature of these aggressive neuroblastomas is the increased occurrence of the oncogene MYCN.
A team led by Dr. Jan Rafael Dörr and Prof. Anton Henssen from the Experimental and Clinical Research Center (ECRC), a joint facility of the Charité and the Max Delbrück Center, have now discovered that the location of this gene plays a key role: If it is located outside the chromosomes, the cancer cells can protect themselves from drug attack by remaining dormant. The researchers propose a new treatment strategy that also targets these dormant tumour cells. Their approach has already proven successful in a mouse model.
Cancer Genes on Small Rings
Neuroblastoma is one of the most common cancers in children. The tumours develop from cells of the sympathetic nervous system, can arise anywhere in the body, and are predominantly found in children under five years of age. “Neuroblastomas in which the MYCN oncogene is detectable were previously considered particularly difficult to treat,” says Jan Dörr, who also works as a paediatric oncologist at the Charité. “We wanted to find out exactly what the gene does in the cells, how it might influence the expression of other genes, and how such tumors can be destroyed more effectively in the future.”
Anton Henssen, also a paediatric oncologist at the Charité, and his team had previously discovered that the oncogene is often not located on the chromosomes, but on much smaller, circular DNA molecules. “When cells divide, this DNA, unlike chromosomal DNA, is distributed randomly among the daughter cells,” explains the scientist. As a result, such neuroblastomas contain cells with both very many and very few MYCN copies.
The dormant cells evade
Jan Dörr and his team further investigated the different tumour cells. “Together with Fabian Coscia’s group, we succeeded in separating cells with many MYCN copies from those with few copies, thanks to a method described for the first time in the study, and then investigated how the protein composition and phenotype of these cells differ from each other,” reports the researcher.
In experiments with cultured tumour cells, mouse models, and patient samples, the researchers subsequently demonstrated that only aggressive cells with many MYCN copies are destroyed by chemotherapy. “Tumour cells with few MYCN copies, on the other hand, survive and simply fall into a kind of deep sleep,” explains Jan Dörr. However, they can awaken from this state through wake-up calls that are not yet fully understood and then contribute to the relapse of the cancer.
An approach also for brain tumours
“There are drugs that specifically target such senescent, i.e., dormant, cells,” says Jan Dörr. In a mouse model, he and his team have shown that combining chemotherapy, which primarily destroys rapidly growing cells with many MYCN copies, with a subsequent drug that attacks the senescent cells, makes neuroblastoma therapy significantly more effective. “Our approach is likely particularly suitable for tumours in which the MYCN gene or other oncogenes are located on the extrachromosomal DNA,” says the scientist. For tumours in which these genes are located on the chromosomes, different strategies must be developed.
First, the researchers now want to systematically search for other drugs that also specifically target dormant tumour cells in human tissue and, if possible, spare healthy cells. “The approach now presented is certainly also interesting for the treatment of other tumours in which cancer genes on the DNA rings are involved,” adds Anton Henssen. These include, for example, the particularly feared brain tumours.
*Montuori G, Tu F et al. Extrachromosomal DNA-driven oncogene dosage heterogeneity promotes rapid adaptation to therapy in MYCN-amplified cancers. Cancer Discov 2025 Aug 07. doi: 10.1158/2159-8290.CD-24-1738
About the Study
The study was jointly led by Prof. Anton Henssen and Dr. Jan Rafael Dörr. Both are physicians at the Department of Paediatrics with a focus on Oncology and Hematology at the Charité. At the ECRC, Jan Dörr leads the research group “Tumour Heterogeneity and Therapy Resistance in Paediatric Tumours,” and Anton Henssen leads the research group “Genomic Instability in Paediatric Tumours.” Joint first authors of the study are Dr. Giuila Montuori, a scientist at the Department of Paediatrics with a focus on Oncology and Hematology at the Charité, and Fengyu Tu, who conducts research in London and China under the direction of Dr. Benjamin Werner and Dr. Huang. Prof. Henssen, Dr. Werner, and Dr. Huang are members of the international Cancer Grand Challenges Team eDyNAmiC, funded by Cancer Research UK and the National Cancer Institute. The Max Delbrück Center’s “Spatial Proteomics” working group led by Dr. Thomas von der Leyen (Max Delbrück Center) also played a significant role. Fabian Coscia.