New research unravels mitochondria's role in breast cancer metastasis

Mitochondria have long been known as the tiny organelles that act as the battery packs inside our cells while also serving as internal sensors and communicators. But relatively little is understood about how their energy-producing activities in soupy cellular interiors impacts metastatic cancer, which occurs when cancerous cells spread in the body.

Now, collaborative research co-led by Dr. Julie St-Pierre's lab at the Faculty of Medicine sheds new light on the mysteries of mitochondrial dynamics and its likely role in the metastatic progression of breast cancer – the most commonly-diagnosed cancer in women across the globe.

Shapeshifting mitochondria continually fuse and divide, but precisely how those dynamics influence metastatic progression has intrigued scientists. In the work published in Science Advances, the uOttawa-led team puts forth compelling evidence that promoting mitochondrial elongation in cancer cells hobbles their ability to metastasize.

The team's insights will certainly be of deep interest to scientists studying mitochondrial dynamics and a range of cancers. Further, this discovery may eventually uncover a therapeutic opportunity for halting breast cancer progression.

Our results suggest that inducing a fused mitochondrial network in breast cancer cells limits their ability to metastasize. This is exciting because metastasis is the main cause of death in patients with cancer." 

Dr. St-Pierre, Professor in the Faculty of Medicine and uOttawa's Interim Vice-President, Research and Innovation

The study's first author is Dr. Lucía Minarrietanorth_eastexternal link, a postdoctoral fellow at the uOttawa Faculty of Medicine who is drilling down on mitochondria and metastasis at the Ottawa Institute of Systems Biology.

She notes that the research team used several different approaches to promote mitochondrial elongation in breast cancer cells to reveal a common signature that would help them figure out which pathways are leading to a decrease in metastasis. This methodical approach was also used to determine clinical relevance.

"When we analyzed the mitochondrial morphology of different breast cancer cell lines, we observed that those with lower metastatic potential tend to have longer mitochondria. This suggests that a fragmented mitochondrial network could be associated with more aggressive presentations of the disease," Dr. Minarrieta says.

With the help of this common elongation signature acting as a sort of a measuring stick, the investigators were able to observe that a higher mitochondrial elongation score was associated with better outcomes in patients with breast cancer. That includes those with more aggressive subtypes.

"We believe that promoting mitochondrial elongation in breast cancer cells could be used during the initial course of treatment to prevent metastatic reoccurrence in the long run," says Dr. St-Pierre, adding that metastatic breast cancer often develops after individuals complete therapy for their initial diagnosis and live cancer-free for a time.

In addition to targeting mitochondrial fission proteins by genetic manipulation in the lab, the team also identified a potentially promising way of inducing elongation in mitochondria using an antirheumatic drug called leflunomide. Marketed under the brand name Arava among others, the drug is approved by the U.S. Food and Drug Administration (FDA) and Health Canada.

The evidence that leflunomide could be repurposed to prevent or delay metastatic disease in patients is a key translational aspect of the study, according to Dr. St-Pierre.

"We would like to explore further the translational aspect of these findings. Eventually, it would be important to perform clinical trials to test the impact of leflunomide on metastasis in cancer patients," says Dr. St-Pierre, whose Faculty of Medicine lab specializes in exploring new ways to reduce metastatic and treatment-resistant disease in women with breast cancer.

The collaborative study was co-led by Dr. Peter Siegel, an expert on cancer metastasis at McGill University, and included contribution from Dr. Mireille Khacho, Associate Professor at the uOttawa Faculty of Medicine and Canada Research Chair in Mitochondrial Dynamics and Regenerative Medicine.

The work was made possible by several core facilities at the University of Ottawa, notably the Metabolomics Core Facility. The team received funding from The Canadian Institutes of Health Research (CIHR).