Neuroblastoma cells. The oncogene MYCN is stained turquoise. Cell nuclei are marked in blue. Pink indicators a change in chromatin, which is attribute of dormant cells. Cells with few copies of the MYCN gene enter a dormant state. Credit score: Giulia Montuori, Charité. The picture was created with the assistance of theAdvanced Mild Microscopy Know-how Platform of the Max Delbrück Heart.
Neuroblastoma generally is a notably insidious most cancers. In about half of all circumstances, tumors regress, even with out remedy. Within the different half, tumors develop in a short time. These tumors typically reply effectively to chemotherapy at first, however often return after one to 2 years. A attribute function of such aggressive neuroblastoma cells is an abnormally excessive variety of copies of the oncogene MYCN.
A group led by Dr. Jan Dörr and Professor Anton Henssen from the Experimental and Medical Analysis Heart (ECRC), a joint establishment of Charité—Universitätsmedizin Berlin and the Max Delbrück Heart, has now found that the situation of the MYCN gene performs an essential position within the aggressiveness of neuroblastoma: Whether it is situated exterior chromosomes, most cancers cells enter a dormant state and thereby render themselves proof against remedy.
In Most cancers Discovery, the analysis group proposes a brand new therapy technique that targets these dormant tumor cells. Their method has already confirmed profitable in a mouse mannequin.
The examine’s first authors are Dr. Giulia Montuori, a scientist on the Division of Pediatric Oncology and Hematology at Charité, the place Dörr and Henssen additionally work as pediatric oncologists, and Fengyu Tu, who conducts analysis below the supervision of Dr. Benjamin Werner and Dr. Weini Huang in each London and China. Henssen, Werner and Huang are members of the worldwide Most cancers Grand Challenges group eDyNAmiC. Dr. Fabian Coscia’s Spatial Proteomics analysis group on the Max Delbrück Heart additionally performed a key position. The examine is a first-rate instance, say Dörr and Henssen, of how worldwide collaboration between medical and analysis groups can profit sufferers.
Most cancers genes on tiny DNA rings
Neuroblastoma is without doubt one of the commonest cancers in kids. The tumors develop from cells of the sympathetic nervous system, can happen wherever within the physique, and largely have an effect on kids below the age of 5.
“Neuroblastomas with the MYCN oncogene have been particularly hard to treat,” says Dörr, Head of the ECRC analysis group Tumor Heterogeneity and Remedy 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.”
Henssen, Head of the ECRC analysis group Genomic Instability in Pediatric Tumors, has beforehand proven that these oncogenes are sometimes not situated on chromosomes in cell nuclei, however somewhat 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. Because of this, neuroblastomas can include a mixture of cells, some with excessive numbers of MYCN genes and others with only a few.
The sleeping cells escape therapy
Dörr and his group investigated the tumor cells additional. “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 fashions and affected person samples, the researchers have been then in a position to present that solely 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. Nonetheless, they’ll awaken from this deep sleep by way of wake-up calls that aren’t but totally understood, after which contribute to the most cancers recurring.
A brand new technique for mind tumors, too
“There are drugs that specifically target senescent, or sleeping, cells,” says Dörr. In mouse fashions, he and his group demonstrated that combining chemotherapy—which eliminates fast-growing cells with many MYCN copies—with a second drug that targets senescent cells can considerably enhance therapy 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, completely different methods will likely be wanted.
Subsequent, the group plans to systematically seek for extra compounds that may selectively assault dormant tumor cells in human tissue whereas sparing wholesome cells. “This approach could also be relevant for other cancers that involve genes located on extra-chromosomal ring-shaped DNA,” Henssen provides—together with dreaded mind tumors.
Extra info:
Giulia Montuori et al, Extrachromosomal DNA-Pushed Oncogene Dosage Heterogeneity Promotes Speedy Adaptation to Remedy in MYCN-Amplified Cancers, Most cancers Discovery (2025). DOI: 10.1158/2159-8290.CD-24-1738
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Concentrating on sleeping tumor cells: Oncogene location could decide neuroblastoma’s resistance to most cancers remedy (2025, August 8)
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