Can small circles of DNA, once dismissed as irrelevant, actually be major contributors to cancer development? Three new research studies suggest that yes, small circular bits of extrachromosomal DNA (ecDNA) are involved in thousands of types of cancer, and they may be targeted with a new therapy. The findings have been reported in three research papers in Nature by an international research group known as eDyNAmiC.
Circles of ecDNA are usually small, but carry a few genes that are often linked to cancer. Cancer-linked genes are sometimes known as oncogenes, and researchers found that when a cell carries several ecDNAs with oncogenes, this boosts cell growth and encourages the cell to regard checkpoints that can stop uncontrolled cell proliferation. At a basic level, cancer is uncontrolled cell growth.
Sometimes ecDNA may also carry genes that encode for proteins that promote cancer development by reducing anti-cancer immune activity.
It was once assumed that few tumor cells carried important ecDNA molecules, but studies have indicated that they are actually crucial to many types of cancer.
The research team analyzed the levels of ecDNA in about 39 different types of tumor cells from about 15,000 patients. This effort showed that about 17 percent of tumor cells carry ecDNA, which is found at higher levels after certain toxic treatments like chemotherapy. The presence of ecDNA was linked to cancer metastasis and poor outcomes.
Some ecDNA molecules were also found to carry enhancer sequences that can boost the activity of genes on other ecDNAs. This process invovles a physical link between two ecDNAs, one of which contains an enhancer.
"The ecDNAs with enhancer elements don't confer any benefit to the cell on their own; they have to work with other ecDNAs to spur cancer cell growth," explained a senior study author Howard Chang, MD, PhD, a professor at Stanford University and a Howard Hughes Medical Institute investigator. "This was kind of a heretical idea."
It would seem that the mere existence of ecDNAs with enhancers are not a problem, said Chang. "But the teamwork and physical connection between different types of circles is actually very important in cancer development."
"We're in the midst of a completely new understanding of a common and aggressive mechanism that drives cancer," said a senior study author Paul Mischel, MD a professor and vice chair of research at Stanford University, among other appointments.
During cell division, ecDNAs can randomly end up in one daughter cell or another, so some cells might carry high levels of ecDNAs and others have little or none. Therefore, some tumor cells will end up with ecDNAs that allow them to resist drug treatment or immune activity, or give them some other advantage so that they continue to proliferate.
The scientists also determined that when ecDNAs are working together during cell division, they will remain linked as they are passed onto daughter cells.
Additional research study revealed that when the activity of a protein called CHK1 was blocked, tumor cells that contain ecDNA will die, and when the activity of CHK1 was halted in a mouse model of gastric tumors with ecDNA, those tumors began to shrink.
Now, there is a CHK1 inhibiting drug in early trials for patients with certain types of cancer that are associated with ecDNAs that carry oncogenes.
"This turns the table on these cancer cells," Chang said. "They are addicted to this excess transcription; they can't stop themselves. We made this into a vulnerability that results in their death."
Sources: Stanford University Medical Center, Hung at al Nature 2024, Tang at al Nature 2024, Bailey et al Nature 2024