Circular DNA – rings of genetic material

How does cancer develop and progress? A team led by pediatric oncologist Dr. Anton G. Henssen has set out to further improve our understanding of these processes. The researcher at the Experimental and Clinical Research Center (ECRC), a joint institution of Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), is also a participant in the BIH Academy’s Clinician Scientist Program. The aim of his project CancerCirculome is to learn more about circular DNA – ring-shaped sections of DNA that that are found inside our cells but outside the chromosomes and appear to play a particular role in cancer. The European Research Council (ERC) has now awarded Anton Henssen a grant worth €1.48 million to set up his research group.

It was only discovered relatively recently that cancer cells have the ability to produce small, ring-shaped sections of extrachromosomal DNA known as circular DNA or ecDNA, which they then reintegrate into the existing genetic material. If the original sequence of DNA segments is disrupted, cell growth can get out of control and cancer can develop. “We have already been able to demonstrate that this occurs more commonly than we believed in neuroblastoma, a cancer that primarily affects children,” confirms Dr. Henssen, who is also a physician at Charité’s Department of Pediatrics, Division of Oncology and Hematology. “We take this as an indication that the presence of circular DNA plays an important role in the remodeling of cancer cell DNA.”

With the launch of CancerCirculome, the pediatric oncologist and leader of an Emmy Noether Independent Junior Research Group wants to work together with his team to find out more about the role of ecDNA in pediatric cancers. “We still don’t know exactly how circular DNA are made and how they multiply. To help us identify the origin of these tiny rings, we will reconstruct the exact DNA sequences they contain,” explains Henssen “To do this, we will identify the molecular factors responsible for the generation and replication of ecDNA at the single-cell level.”

The team hopes to uncover previously unknown mechanisms that cause cells to lose control over their growth. “These mechanisms could become new targets in diagnosis and treatment – not only for cancers in children, but as a basic principle for all cancers,” says Henssen, who is also a scientist at the German Cancer Consortium (DKTK). The scientists will now use the CRISPR method to target and manipulate ecDNA segments in individual human cells and cancer cells in order to demonstrate the biological effects of DNA circularization and its reintegration. The researchers also want to study the presence, behavior, and genomic integration of circular DNA at the single-cell level during cancer treatment. The aim is to uncover how these ring-shaped DNA sections trigger the onset of cancer and to determine the mechanisms responsible for their reintegration into the chromosome.

Anton Henssen hopes the resulting knowledge will find clinical application, in line with the BIH’s mission of turning research into health: “We hope to find new predictive markers that can aid in the personalized diagnosis, risk assessment and treatment of cancers.” The long-term goal is to contribute to the understanding of cancer in general and to support clinical trials involving personalized treatments for children with difficult-to-treat cancers.

ERC Starting Grant
The European Research Council (ERC) provides support for early career researchers as part of the EU’s Horizon 2020 research and innovation program. The grant, which is intended to support the establishment of a new research group at the Department of Pediatrics, Division of Oncology and Hematology, and the Experimental and Clinical Research Center (ECRC), totals €1.48 million over the next five years.

BIH Charité Clinician Scientist Program
The program, which is offered by the Berlin Institute of Health (BIH) and Charité, enables physicians to pursue a structured residency, with time set aside for clinical and basic research.