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How cancer genes become independent

05.05.2023 / Sometimes a tumor suddenly starts growing rapidly or becomes resistant to cancerdrugs. This can be caused by a cancer gene “striking out on its own” in ring shapes. ECRC-scientist Anton Henssen described how these DNA rings arise and continue to develop in the journal “Nature Genetics”.

Considered one of the biggest challenges in cancer research, DNA rings are tiny loops of genetic material floating around the nucleus of the cell by the hundreds, detached from the chromosomes. Nearly one-third of all tumors in pediatric and adult patients have DNA rings inside their cells – and those tumors are almost always highly aggressive. Ring-shaped DNA, termed extrachromosomal DNA (ecDNA), is also often implicated when a tumor develops resistance to a previously effective medication. Researchers around the world hope to identify new approaches to treating cancer by studying this specific form of genetic information. However, ecDNA does not always have a detrimental effect on cancer growth.

“To tell the difference between dangerous and harmless DNA rings and be able to trace their evolution within the tumor, we have to look at the tissue one cell at a time,” explains the head of the study, Professor Anton Henssen. He works at the Department of Pediatric Oncology and Hematology at Charité and does research at the Experimental and Clinical Research Center (ECRC), a joint institution of Charité and the Max Delbrück Center. Together with his team, he has now developed a technology that can read the genetic code of the existing DNA rings for each individual cell. At the same time, it tells which genes are active on the rings. “This lets us simply count how many cells in the tumor are home to a specific ring,” Henssen says. “If there aren’t many, then that ring is not highly relevant to the growth of the cancer. But if there are a lot of them, it evidently gives a tumor cell a selective advantage.”

Which DNA rings spur tumor growth?

The researchers initially used the new method to take a snapshot of all DNA rings in cultured neuroblastoma cells. Neuroblastoma is a form of highly malignant cancer that is especially prevalent in very young children. The research showed that no two cancer cells are alike – where one might have 100 DNA rings floating around, the next might have 2,000. The rings also vary greatly in size, with the smallest of them consisting of only 30 genetic components and the largest comprising over a million.

“The big DNA rings are loaded with cancer genes originating in the chromosomes of the cell,” explains Rocío Chamorro González, the study’s first author, who works in Henssen’s lab. “The ring shape lets them circumvent the classic laws of genetics, so they take on a kind of autonomy. These cancer genes have struck out on their own, if you will. We are only just starting to understand the ramifications. In our study, we found the large DNA rings in many neuroblastoma cells, so they are evidently spurring cell growth. The small rings were only found in isolation, so they are probably not very relevant to the cancer cells.”

Evolution of an independent cancer gene

To understand how an ecDNA originates in the first place and then evolves within a tumor, the second step for the research group was to analyze a pediatric neuroblastoma – cell by cell. Their findings suggest that MYCN, a known cancer gene, first detached from its chromosome of origin and formed a ring shape at the start of the tumor’s growth in this case. Then two of the rings merged to form a larger one, which went on to lose a shorter segment and then a longer one. “The last ring seems to have been the first to confer a growth advantage, because it is the only one that appears in many of the neuroblastoma cells,” Henssen says. “This shows that the cancer gene not only became independent through these processes, but also continued to ‘improve.’”

This kind of insight into the evolution of DNA rings within a tumor would have been impossible if not for the newly developed method. The team of researchers now plans to use the same method to reconstruct the stages of development in further cases of cancer.

 

Source: Joint press release of Charité - Universitätsmedizin Berlin and the Max Delbrück Center
How cancer genes become independent