Aggressive tumors often contain large amounts of extrachromosomal DNA, which can promote cancer. An international team led by Anton Henssen has identified a potential target to improve patient outcomes by removing this DNA from cancer cells.
Cells from rapidly growing, highly metastatic tumors often contain numerous rings of extrachromosomal DNA (ecDNA), which frequently carry oncogenes that promote cancer. Researchers have long sought vulnerabilities in these DNA rings to stop their harmful activity.
Dr. Anton Henssen, Group Leader of the Genomic Instability in Pediatric Tumors lab at the Experimental and Clinical Research Center, a joint institution of Charité – Universitätsmedizin Berlin and the Max Delbrück Center, has discovered that the DNA rings lose their activity when they become trapped outside the cell nucleus in micronuclei. This process also occurs naturally in cancer cells, and active compounds that drive ecDNA into micronuclei may help treat some metastatic cancers.
The study, conducted as part of the international Cancer Grand Challenges initiative, was led by Dr. Anton Henssen, Dr. Howard Chang, and Dr. Paul Mischel. They used a laser-assisted method to sequence the genetic material of individual micronuclei and found that they are primarily filled with ecDNA.
Micronuclei are visible under a light microscope and are commonly found in cancer cells. The team discovered that the structure of the DNA rings changes once they are inside micronuclei, making it impossible for the cell to read the genes carried on these rings or translate them into proteins.
This finding is important for both the diagnosis and prognosis of cancer, as cancer cells containing many micronuclei have a significant survival disadvantage. The team showed that survival was strongly associated with the presence of micronuclei in a cohort of several hundred patients with neuroblastoma.
The researchers are now investigating ways to prevent DNA rings from hitchhiking into new nuclei during cell division. They aim to ensure that as many rings as possible end up trapped inside micronuclei, where they can no longer drive cancer growth.
Dr. Anton Henssen notes that they already know of drugs that block the proteins ecDNA uses to attach itself to chromosomes. His company, Econic Bioscience, is actively searching for additional active ingredients that transport the destructive DNA rings into the micronuclei as quickly as possible.
The study was funded by Cancer Grand Challenges and the German Research Foundation.
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