Cells from rapidly growing, highly metastatic tumors often contain numerous rings of extrachromosomal DNA (ecDNA). This circular DNA frequently carries oncogenes — genes that promote cancer. Researchers have long sought vulnerabilities in these DNA rings in an effort to stop their harmful activity.

An international team led by Prof. Anton Henssen, Group Leader of the Genomic Instability in Pediatric Tumors lab at the Experimental and Clinical Research Center, a joint institution of Charité and the Max Delbrück Center as well as scientist in the German Cancer Consortium, partner site Berlin, has now identified a potential target. As the researchers report in their new study, the DNA rings lose their activity when they become trapped outside the cell nucleus in micronuclei — a process that also occurs naturally in cancer cells. Consequently, researchers have been searching for active compounds that drive ecDNA into micronuclei.

Hitchhiking during cell division

When a cell divides, its chromosomes are normally distributed evenly between two daughter cells. ecDNA behaves differently. “These DNA rings lack the structures needed for orderly transport,” Anton Henssen explains. “Instead, they attach themselves to chromosomes and essentially hitchhike into the new cells.” Some rings succeed, while others do not. “The less successful ones become trapped in micronuclei,” he says.

Scientists have documented the existence of micronuclei, which are visible under a light microscope and are commonly found in cancer cells, for many years. Using a laser-assisted method developed with Prof. Ana Pombo at the Max Delbrück Center, Henssen’s team sequenced the genetic material of individual micronuclei.

“We found that micronuclei are primarily filled with ecDNA,” says Robin Xu in Henssen’s lab and one of the study’s three first authors. “This means we can estimate the amount of ecDNA in cancer cells simply by observing visible micronuclei.”

The researchers also discovered that the structure of the DNA rings changes once they are inside micronuclei. “As a result, the cell can no longer read the genes carried on these rings or translate them into proteins,” adds Lotte Brückner, who shares first authorship with Robin Xu. “Cancer cells containing many micronuclei therefore have a significant survival disadvantage, making this finding important for both the diagnosis and prognosis of cancer.”

Preventing DNA rings from hitchhiking

Using a well-characterized cohort of several hundred patients with neuroblastoma, Anton Henssen and his colleagues showed that survival was strongly associated with the presence of micronuclei. “The more micronuclei containing large amounts of circular DNA we found in tumor cells, the more successful the patients’ treatment was,” he says.

The researchers are now investigating ways to prevent DNA rings from hitchhiking into new nuclei during cell division. Their goal is to ensure that as many rings as possible end up trapped inside micronuclei, the cellular “prisons,” where they can no longer drive cancer growth.

“We already know of drugs that block the proteins ecDNA uses to attach itself to chromosomes,” Anton Henssen says. Econic Bioscience, a company he founded in London in 2022 along with the former founders of CRISPR therapeutics Dr. Rodger Novak and Shaun Foy, is actively searching for additional active ingredients that transport the destructive DNA rings into the micronuclei as quickly as possible – and securely seal them there.

*Brückner L, Xu R, Tang J et al. Micronuclear ecDNA constrains tumor cell fitness and is associated with favorable patient survival. Nat Genet 2026 Oct 12. doi: 10.1038/s41588-026-02782-w

About the study

In addition to Prof. Anton Henssen, the study’s senior authors are Prof. Howard Chang and Prof. Paul Mischel of Stanford University in California. Since December 2024, Howard Chang has served as Chief Scientific Officer at Amgen, one of the world's leading biotechnology companies. Paul Mischel leads the eDyNAmiC team within the international Cancer Grand Challenges initiative, which seeks to better understand the key role of circular DNA in cancer. The current study was conducted as part of that project. The study was additionally funded by Cancer Grand Challenges and the German Research Foundation (DFG) Collaborative Research Center (CRC) 1588, “Deciphering Evolutionary Mechanisms in Neuroblastoma.” Anton Henssen is the spokesperson for CRC 1588.

SOURCE: Charité

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