Yale researchers developed a new approach to simultaneously investigate hundreds of mutation combinations for their ability to drive lung metastasis.

The ability of cancer to establish itself in distant parts of the body—called metastasis—causes 90% of deaths from solid tumors. Metastasis is the result of complex genetic interactions that have proven difficult for scientists to study. Now Yale researchers have devised a way to identify some of the most dangerous of those interactions, they report April 8 in the journal Nature Methods.

“Metastasis is a complicated process; it is not like one gene controls everything,” said Sidi Chen, assistant professor of genetics and senior author of the paper. “There are hundreds of thousands of potential genetic interactions, and it has been hard to know which ones are most important.”

Using CRISPR gene editing technology, the researchers created a library with almost 12,000 unique constructs (DNA that can knock out genes in a cell) that target 325 pairs of genes implicated in metastasis in human cancers. Several of these pairings of mutant genes caused aggressive spread of tumors in mice, they found.

“With our approach, we were able to pinpoint specific mutation combinations that drive metastasis,” said Ryan Chow, a third-year MD/PhD student and co-first author of the study. “This is an important step toward understanding the complex genetic interactions underlying cancer progression.”

The technology may one day enable scientists to study combinations of metastasis-linked genes identified from individual patients and even dissect the interactions of three or even four of these genes simultaneously, say the authors. Ultimately, understanding these genetic interactions may help scientists devise new strategies to halt the spread of a variety of different cancers, they note.

Yale’s Chow, Guangchuan Wang, and Lupeng Ye are co-first authors of the study. Chen is affiliated with Yale’s Department of Genetics, the Yale Cancer Center, the Yale Stem Cell Center, and the Systems Biology Institute and Center for Cancer Systems Biology at West Campus. Primary funding for the study came from the National Institutes of Health.

Chen’s lab also receives funding from other agencies such as the Department of Defense, American Association for Cancer Research, Cancer Research Institute, Damon Runyon, Melanoma Research Alliance, St. Baldrick’s Foundation, Breast Cancer Alliance, The Mary Kay Foundation, The V Foundation, Ludwig Family Foundation, Sontag Foundation, and Chenevert Family Foundation.