Scientists have recently been learning more about the importance of small bits of circular genetic material known as extrachromosomal DNA (ecDNA). These little circles of DNA can hitch a ride with chromosomes as cell division is happening, to get into the daughter cells that are produced during cell division. The ecDNA is taking advantage of a process that normally helps cells maintain their identity through generations. But ecDNA can promote the growth of cancer. So disrupting or blocking their link to chromosomes could potentially be a totally new way to treat cancer. New insights into ecDNA have been reported in Nature.
"Unfortunately, ecDNAs have developed a crafty mechanism that allows them to wreak havoc on human health," explained co-senior study author Paul Mischel, MD, a professor at Stanford University, among other appointments. "They are using nature's own method of gene expression and cell fate to ensure they are safely distributed into the next generation of cells and not lost into the cytoplasm or extracellular space when a cell divides."
ecDNAs can form when chromosomal DNA is being copied for cell division, or repaired. Pieces of linear DNA can be released, which can then link together, and have the potential to form circular structures.
Cancer cells often contain multiple ecDNAs that carry cancer-promoting genes called oncogenes. These genes can boost cell growth and help it to evade checkpoints that stop uncontrolled cell division. ecDNA can also carry genes that suppress anti-cancer immune mechanisms.
Previous work has shown that ecDNA helps cells become cancer cells, and that about 17% of tumors carry ecDNA. Metastasis and poor outcomes have also been associated with the presence of ecDNA.
To learn how ecDNAs were associating with chromosomes, the researchers created a screening tool they called Retain-seq. In this method, genomic DNA is cut into small segments, and added to bacterial DNA. These engineered DNA molecules were then put into human cells.
The investigators found that this engineered DNA could hang around for many subsequent cell generations. These sequences were termed retention elements, and over 14,000 were identified. Six of them were very similar to ecDNAs that have been identified in cancer cells, and the researchers analyzed them in further detail.
They found that ecDNAs can be inherited in daughter cells, but in a random way. So there are some daughter cells that hold onto most of the ecDNA from parent cell while others keep very little of it. This process allows cancer cells to evolve quickly and adapt to new conditions, such as those introduced by cancer treatments.
The work also showed that epigenetic tags known as methyl groups, which can affect gene expression, were also usually missing from retention elements. When the investigators added methyl groups to ecDNAs in cancer cells growing in culture, the ecDNA stopped associating with chromosomes and many fewer were present in daughter cells. This seemed to disrupt cancer cell growth in culture, possibly because the cells were missing the immunosuppressive genes and oncogenes provided by ecDNAs.
"This shows the remarkable specificity of this process," Mischel said. "It's not due to random stickiness. The ecDNAs are actively using cellular machinery that evolved for one purpose: maintaining a cell's identity through generations to ensure their own survival. This is a remarkable co-opting of nature's own mechanisms. But it's also a weakness; if we can interrupt that process, we unlock new therapeutic opportunities for many deadly cancers."
Sources: Stanford University, Nature