Mitochondrial DNA may play more important role in metastatic cancer than previously thought

DNA found in the mitochondria may play a more significant role in metastatic cancer than originally thought.

Most research efforts that study the origins of cancer metastasis focus on the nuclear genome, or the DNA contained in the nucleus. The human nuclear genome consists of 46 chromosomes containing 3.3 billion nucleotides. Human mitochondrial DNA, on the other hand, accounts for a much smaller portion of our total DNA and is comprised of only one chromosome.

Despite its small size, mitochondria are known as the "powerhouses" of the cell, taking in nutrients and generating energy. What's more, researchers at The University of Kansas Cancer Center believe it may contain information that could help determine the likelihood of cancer metastasizing. Their findings recently made the front page of Cancer Research, a prestigious scientific journal.

"A lot of people have dismissed mitochondrial DNA as superfluous. But our research suggests otherwise," says Amanda Brinker, PhD, lead author on the publication. The team's research was spurred by an NIH study published in 2006, which found that specific mouse strains when bred together had varying amounts of metastasis depending on their maternal lineage. Brinker conducted the research while pursuing her doctorate. At the time, she was a member of Danny Welch's lab, which focuses on metastasis in breast cancer. Welch, PhD, is associate director of Basic Science at KU Cancer Center.

"Unlike nuclear DNA, which comes from both parents, mitochondrial DNA is inherited solely from the mother," Brinker says.

To better understand the relationship between mitochondrial DNA and metastasis, the team utilized a novel mouse model. Called the Mitochondrial Nuclear Exchange Mouse Model, "MNX" for short, an intact nucleus containing nuclear DNA from one mouse strain is inserted into fertilized mouse cells that contain different types of mitochondrial DNA but no nucleus. The result is a pure population containing identical nuclear DNA, allowing researchers to connect effects to the mitochondrial DNA.

"Metastasis is a process that involves multiple organ systems throughout the body and so is not well-modeled in cells in a dish. A whole organism model is needed," Brinker says "Models used in other studies have always had some degree of blended nuclear DNA so we could never tell if an effect was due to the nuclear DNA or the mitochondrial DNA."

Welch's team exposed different mouse models including MNX to the HER2 breast cancer oncogene and then monitored for initial tumor formation and subsequent metastasis. "We gave them all the same amount of time for tumors to metastasize. Yet, each set followed a different schedule of tumor formation," Brinker says. "It demonstrates that mitochondrial DNA alters the way initial tumors arise and then metastasize, as well as the number and size of those tumors."

Furthermore, additional research shows not only how mitochondrial DNA affects the entire process of metastasis, but that outcomes can vary depending on the type of cancer. Brinker adds that this is the first step to better understanding mitochondrial DNA's role in cancer, which can lead to more precise personalized medicine.

"Right now, we are able to sequence a tumor and select the most effective therapies based on the tumor and DNA. This research shows that we could be missing a big piece of the puzzle – mitochondrial DNA," Brinker says. "Eventually, we may be able to better understand who is at greater risk for metastasis and subsequently treat them with personalized therapies while sparing others from unnecessary therapies. This discovery has opened up some many doors."