Illuminating metastasis
Mom’s the word

For Danny Welch, Ph.D., of Cancer Biology, research has long been all about metastasis – understanding why some tumors are sneakier than others in invading new areas of the body. More recently, however, another “M” word has significantly occupied his attention: mitochondria, those miniscule structures that fuel cellular function. Serendipitously, some of the latest findings from Welch and his crew suggest that both metastasis and mitochondria are linked in more ways than one.   

Molecular Maya-modeled landscape depicting a single mitochondrion colored light brown (left half of image). 

In August 2013, Welch and Scott Ballinger, Ph.D., a colleague at the University of Alabama at Birmingham, co-authored a publication in Biochemical Journal showing for the first time that the diminutive mitochondrial genome, entirely separate from the rest of a cell’s DNA and with a strictly maternal inheritance pattern, might well have a not-so-tiny role in predisposition toward heart disease and metastatic cancer. The collaboration between Welch and Ballinger first took root in data from Kent Hunter, Ph.D., of the National Cancer Institute. Having mated a male mouse carrying a breast tumor oncogene with 60 different strains of female mice, Hunter was trying to figure out why some of the crossbred offspring were highly prone to metastasis, while in others, the tendency for their induced breast tumors to spread to the lungs was almost completely stifled.

“Scott and I had a series of hallway conversations and, along the way, two things occurred to us,” Welch says. “The first was a fact I hadn’t thought about in awhile – that mitochondrial DNA is maternally inherited. The second was that Kent’s observations came from breeding one male mouse with many different females. Could the next generation’s varying likelihood of metastasis have come from Mom, through the mitochondria?”

To probe their hunch, Welch and Ballinger developed mitochondrial-nuclear exchange (MNX), a method that allows researchers to determine whether a given trait tracks with the nucleus or the mitochondria. Because Ballinger’s primary research interest is in heart disease risk – and he had already been wondering if mitochondrial DNA could be a plausible culprit here – they began by engineering MNX mice with interchanged nuclear and mitochondrial genomes from two strains: C57BL/6, which is prone to heart disease; and C3H, which is resistant. They then exposed the mice to various forms of cardiac stress. 

“We found that MNX mice with C57BL/6 nuclear DNA and a C3H mitochondrial background had different energy metabolism; they were also much less sensitive to conditions capable of inducing heart failure,” Welch says. MNX mice created through the opposite exchange, meanwhile, proved more vulnerable to heart failure. The researchers speculate that cytochrome oxidase III, a mitochondrial protein central to energy metabolism – which they’ve found differs by a single-base DNA tweak in both mouse strains – could be involved, with this minute change possibly altering COIII’s shape and activity. 

Interestingly, C57 mice are far less susceptible to metastatic cancer, even while being prone to heart trouble. So Welch and Ballinger have been tinkering with other MNX mice in additional experiments. These bear the breast tumor oncogene à la Kent Hunter’s research alongside either the C57 mitochondrial genome or mitochondrial DNA from a mouse strain prone to metastasis. Preliminary evidence indicates a reduced metastatic burden, or total tumor mass, in MNX mice with the C57 mitochondrial genome, and further research is underway.

“I think we’re learning that instead of unidirectional signaling from the nucleus to the rest of the cell, there’s a language of communication involving the mitochondria that hasn’t been fully appreciated,” Welch says. “It comes down to a change in perspective – no longer should anyone trying to do so-called precision medicine draw conclusions based solely on nuclear DNA.”

A second publication from Welch’s crew, in an upcoming issue of Cancer Research, illuminates another way in which mitochondria and metastasis may be linked: through the relationship between KiSS1, a key metastasis suppressor originally discovered by Welch in 1996, and PGC1α, a protein and master regulator of mitochondrial biogenesis, or production of these energy factories in cells.

KiSS1, Welch explains, promotes the expression of PGC1α, leading to more mitochondria along with greater utility of the oxygen-consuming route preferred by normal cells in generating energy. Removing PGC1α from the picture not only reduced mitochondrial numbers, the researchers observed, it also ramped up the Warburg effect – energy metabolism via a different pathway producing lactic acid, preferred by cancer cells – and effectively quashed KiSS1’s function in suppressing metastasis. 

Basically, it appears that KiSS1’s ability to keep a lid on tumor invasion involves, at least partially, its role in regulating mitochondria through PGC1α. It’s the first time such a direct relationship between metastasis suppression and metabolism has been established. But just how this relates – if at all – to the implication of mitochondrial DNA in a person’s susceptibility to the likes of heart disease and metastasis remains unclear.

“Right now, these are simply two separate observations of the potential importance of mitochondria – both genome and function – in influencing the spread of cancer,” Welch says. “But it could lead to a new subfield of research, with scientists taking a much closer look at where mitochondria and the likelihood of metastasis might intersect.”

Funding sources for this research

  • NIH RO1 CA134981: “KiSS1: Defining Mechanisms for Anti-Metastatic Therapy”
  • NIH RO1 HL103859: “Mitochondrial Nuclear Interactions and CVD Susceptibility”
  • Susan G. Komen for the Cure, Scientific Advisory Council (SAC110037): “Regulation of Metastasis by Mitochondrial DNA”
  • U.S. Army Medical Research Defense Command, W81XWH-07-1-0540d: “Mitochondrial-Nuclear Compatibility in Metastatic Susceptibility” (Concept award)
  • National Foundation for Cancer Research (Center for Metastasis Research)

Relevant publications

  • Fetterman JL et al, “Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload.” Biochemical Journal (Oct 2013).
  • Beck BH, Welch DR, “The KiSS1 metastasis suppressor: a good night kiss for disseminated cancer cells.” Eur J Cancer (May 2010).