Stanford researchers unveil the key role of extrachromosomal DNA in cancer

A trio of research papers from Stanford Medicine researchers and their international collaborators transforms scientists' understanding of how small DNA circles -; until recently dismissed as inconsequential -; are major drivers of many types of human cancers.

"We're in the midst of a completely new understanding of a common and aggressive mechanism that drives cancer," said Mischel, who holds the Fortinet Founders Professorship. "Each paper alone is noteworthy, and taken together they represent a major inflection point in how we view cancer initiation and evolution." Mischel is also an institute scholar at Stanford Medicine's Sarafan ChEM-H.

Those featured circles, ecDNAs, are small and often contain a few genes on their circular DNA. Frequently, these genes are cancer-associated genes called oncogenes. When a cancer cell contains multiple oncogene-encoding ecDNAs, they can supercharge the cell's growth and allow it to evade internal checkpoints meant to regulate cell division. The ecDNAs also sometimes encode genes for proteins that can tamp down the immune system's response to a developing cancer -; further advantaging tumor growth.

Greater prevalence than previously thought

The researchers also showed that the circles can contain not just cancer-driving oncogenes and genes that modulate the immune response, but also that others can contain only DNA sequences called enhancers that drive the expression of genes on other circles by linking two or more ecDNAs together.

Howard Chang, MD, PhD, professor of dermatology and genetics, the Virginia and D.K. Ludwig Professor in Cancer Research and a Howard Hughes Medical Institute investigatorThis was kind of a heretical idea. 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. If looked at through a conventional lens, the presence of ecDNAs that solely encode enhancers wouldn't seem to be a problem. But the teamwork and physical connection between different types of circles is actually very important in cancer development."

"This study is a tour de force of data gathering and analysis," Mischel said. "We learned critical lessons about which cancer patients are affected and what genes or DNA sequences are found in ecDNAs. We identified the genetic backgrounds and mutational signatures that give us clues as to how cancers originate and thrive."

Mischel and Chang are the co-senior authors of the second paper that studied how the ecDNA circles are segregated into daughter cells when cancer cells divide. Typically, ecDNAs segregate randomly during cell division. As a result, some new cells could have many ecDNAs while their sister cells had none. This kind of genetic roll of the dice increases the odds that at least some population of cells in the tumor will have the right combination of ecDNAs to evade environmental or drug challenges and contributes to the development of drug resistance.

A new take on peas

"This upends Gregor Mendel's rule of independent assortment of genes that aren't physically linked by DNA sequences," Mischel said, referring to the biologist and Augustinian friar who first described how traits are inherited during his studies of pea plants in the 1860s. "It's really stunning and an enormous surprise."

"Daughter cells that repeatedly inherit particularly advantageous combinations of ecDNA circles should be rare if the segregation of each type of circle is truly random," Chang said. "But this study showed that we were seeing many more of these 'jackpot events' than would be expected. It's like getting a good hand in poker. Cancer cells that get dealt that good hand over and over have a huge advantage. Now we understand how this happens."

"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."

Currently in trials

"These papers represent what can happen when researchers from many different labs come together with a common goal," Mischel said. "Science is a social endeavor and together, through many avenues of converging data from wildly different sources, we've shown that these findings are real and important. We are going to continue exploring the biology of ecDNAs and use that knowledge for the benefit of patients and their families."

Mischel and Chang are scientific co-founders of Boundless Bio, a San Diego-based oncology company developing cancer therapeutics based on ecDNA biology. Boundless Bio is the sponsor of a phase 1/2 study of an inhibitor of CHK1 in people with locally advanced or metastatic solid tumors with oncogene amplifications.

Through Cancer Grand Challenges team eDyNAmiC is funded by Cancer Research UK and the National Cancer Institute, with generous support to Cancer Research UK from Emerson Collective and The Kamini and Vindi Banga Family Trust.

Source:

Stanford Medicine

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