Targeting sleeping tumor cells

Neuroblastoma, a cancer mainly affecting children, is often difficult to treat. A team led by Jan Dörr and Anton Henssen at the Experimental and Clinical Research Center report in “Cancer Discovery,” a potential reason treatment sometimes fails and a new strategy to combat particularly resistant tumors.

Joint press release by the Max Delbrück Center

and Charité - Universitätsmedizin Berlin

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 Dörr and Professor Anton Henssen from the Experimental and Clinical Research Center (ECRC), a joint institution of Charité - Universitätsmedizin Berlin 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. In Cancer Discovery, a journal of the American Association for Cancer Research, the research team proposes a new treatment strategy that targets these dormant tumor cells. Their approach has already proven successful in a mouse model.

The study’s first authors are Dr. Giulia Montuori, a scientist at the Department of Pediatric Oncology and Hematology at Charité, where Dörr and Henssen also work as pediatric oncologists, and Fengyu Tu, who conducts research under the supervision of Dr. Benjamin Werner and Dr. Weini Huang in both London and China. Henssen, Werner and Huang are members of the international Cancer Grand Challenges team eDyNAmiC, which is funded by Cancer Research UK and the U.S. National Cancer Institute. Dr. Fabian Coscia’s Spatial Proteomics research group at the Max Delbrück Center also played a key role. The study is a prime example, say Dörr and Henssen, of how international collaboration between clinical and research teams can benefit patients.

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 Dörr, Head of the ECRC research group Tumor Heterogeneity and Therapy Resistance in Pediatric Tumors. “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.

Henssen, Head of the ECRC research group Genomic Instability in Pediatric Tumors, 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,” Henssen 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

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,” Dörr 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,” explains 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 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 Dörr. 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,” Henssen adds­ – including dreaded brain tumors.

Max Delbrück Center 

The Max Delbrück Center for Molecular Medicine in the Helmholtz Association aims to transform tomorrow’s medicine through our discoveries of today. At locations in Berlin-Buch, Berlin-Mitte, Heidelberg and Mannheim, our researchers harness interdisciplinary collaboration to decipher the complexities of disease at the systems level – from molecules and cells to organs and the entire organism. Through academic, clinical, and industry partnerships, as well as global networks, we strive to translate biological discoveries into applications that enable the early detection of deviations from health, personalize treatment, and ultimately prevent disease. First founded in 1992, the Max Delbrück Center today inspires and nurtures a diverse talent pool of 1,800 people from over 70 countries. We are 90 percent funded by the German federal government and 10 percent by the state of Berlin.