Neuroblastoma can be a particularly insidious cancer. In about half of all cases, tumors regress, even without therapy. In the other half, tumors grow very quickly. These tumors often respond well to chemotherapy at first, but usually return after one to two years. A characteristic feature of such aggressive neuroblastoma cells is an abnormally high number of copies 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 institution of Charité and the Max Delbrück Center, has now discovered that the location of the MYCN gene plays an important role in the aggressiveness of neuroblastoma: If it is located outside chromosomes, cancer cells enter a dormant state and thereby render themselves immune to therapy. The research team propose a new treatment strategy that targets these dormant tumor cells. Their approach has already proven successful in a mouse model.

Cancer genes on tiny DNA rings

Neuroblastoma is one of the most common cancers in children. The tumors develop from cells of the sympathetic nervous system, can occur anywhere in the body, and mostly affect children under the age of five. “Neuroblastomas with the MYCN oncogene have been particularly hard to treat,” says Jan Dörr, who also works as a pediatric oncologist at Charité. “We wanted to find out exactly what the gene does in cancer cells, how it might influence the expression of other genes and how tumors can be destroyed more effectively in the future,” he explains.

Anton Henssen, also a pediatric oncologist at Charité and Scientist at the German Cancer Consortium (DKTK), has previously shown that these oncogenes are often not located on chromosomes in cell nuclei, but rather on many small, ring-shaped DNA molecules inside tumor cells. “When these cells divide, this DNA is distributed randomly to daughter cells – unlike chromosomal DNA,” the researcher explains. As a result, neuroblastomas can contain a mix of cells, some with high numbers of MYCN genes and others with very few.

The sleeping cells escape treatment

Jan Dörr and his team investigated the tumor cells further. “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 investigating how the composition of the proteins and the phenotype of these cells differ from one another,” he explains.

In experiments with cultured tumor cells, mouse models and patient samples, the researchers were then able to show that only aggressive cells with many MYCN copies are destroyed by chemotherapy. “Tumor cells with few MYCN copies, on the other hand, survive and merely enter into a kind of deep sleep,” says Jan Dörr. However, they can awaken from this deep sleep through wake-up calls that are not yet fully understood, and then contribute to the cancer recurring.

A new strategy for brain tumors, too

“There are drugs that specifically target senescent, or sleeping, cells,” says Jan Dörr. In mouse models, he and his team demonstrated that combining chemotherapy – which eliminates fast-growing cells with many MYCN copies – with a second drug that targets senescent cells can significantly improve treatment outcomes for neuroblastoma. “Our approach is likely suitable only for tumors in which the MYCN gene or other oncogenes are located on extrachromosomal DNA,” says the researcher. For tumors with chromosomal oncogenes, different strategies will be needed.

Next, the team plans to systematically search for additional compounds that can selectively attack dormant tumor cells in human tissue while sparing healthy cells. “This approach could also be relevant for other cancers that involve genes located on extra-chromosomal ring-shaped DNA,” Anton Henssen adds – including dreaded brain tumors.

Link to original press release

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