Neuroblastoma generally is a notably insidious most cancers. In about half of all instances, 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 normally 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 workforce led by Dr. Jan Dörr and Professor Anton Henssen from the Experimental and Scientific Analysis Heart (ECRC), a joint establishment of Charité—Universitätsmedizin Berlin and the Max Delbrück Heart, has now found that the placement of the MYCN gene performs an necessary position within the aggressiveness of neuroblastoma: Whether it is situated outdoors chromosomes, most cancers cells enter a dormant state and thereby render themselves proof against remedy.
In Most cancers Discovery, the analysis workforce proposes a brand new therapy technique that targets these dormant tumor cells. Their method has already confirmed profitable in a mouse mannequin.
The research’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 beneath 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 workforce eDyNAmiC. Dr. Fabian Coscia’s Spatial Proteomics analysis group on the Max Delbrück Heart additionally performed a key position. The research is a main 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 likely one of the commonest cancers in youngsters. The tumors develop from cells of the sympathetic nervous system, can happen wherever within the physique, and principally have an effect on youngsters beneath the age of 5.
“Neuroblastomas with the MYCN oncogene have been notably onerous to deal with,” says Dörr, Head of the ECRC analysis group Tumor Heterogeneity and Remedy Resistance in Pediatric Tumors. “We wished to search out out precisely what the gene does in most cancers cells, the way it would possibly affect the expression of different genes and the way tumors may be destroyed extra successfully sooner or later.”
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 quite on many small, ring-shaped DNA molecules inside tumor cells.
“When these cells divide, this DNA is distributed randomly to daughter cells—not like chromosomal DNA,” Henssen explains. In consequence, neuroblastomas can comprise 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 workforce investigated the tumor cells additional. “Along with Fabian Coscia’s group, we succeeded in separating cells with many MYCN copies from these with few copies, because of a way described for the primary time within the research, after which investigating how the composition of the proteins and the phenotype of those cells differ from each other,” Dörr explains.
In experiments with cultured tumor cells, mouse fashions and affected person samples, the researchers have been then capable of present that solely aggressive cells with many MYCN copies are destroyed by chemotherapy.
“Tumor cells with few MYCN copies, then again, survive and merely enter right into a type of deep sleep,” explains Dörr. Nonetheless, they’ll awaken from this deep sleep by way of wake-up calls that aren’t but absolutely understood, after which contribute to the most cancers recurring.
A brand new technique for mind tumors, too
“There are medicine that particularly goal senescent, or sleeping, cells,” says Dörr. In mouse fashions, he and his workforce 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 method is probably going appropriate just for tumors wherein the MYCN gene or different oncogenes are situated on extrachromosomal DNA,” says Dörr. For tumors with chromosomal oncogenes, totally different methods can be wanted.
Subsequent, the workforce plans to systematically seek for further compounds that may selectively assault dormant tumor cells in human tissue whereas sparing wholesome cells. “This method may be related for different cancers that contain genes situated 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
Quotation:
Focusing on sleeping tumor cells: Oncogene location might decide neuroblastoma’s resistance to most cancers remedy (2025, August 8)
retrieved 10 August 2025
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