Breast Cancer Cells Steal Mitochondria from Neurons to Fuel Metastasis

To survive in ever-changing conditions in the body, cancer cells often need to alter their metabolism.¹ This ability to adapt is especially critical for their spread to other parts of the body.

As “powerhouses of the cell,” mitochondria have been linked to metabolic reprogramming and disease progression in various types of cancer.² Over the years, scientists have found that cancer cells can steal mitochondria from other cells, including fibroblasts, macrophages and T cells.^3-6

In a recent Nature study, researchers led by Gustavo Ayala from the University of Texas Health Science Center at Houston and Simon Grelet from the University of South Alabama discovered that breast cancer cells can also steal mitochondria from neurons. The researchers found that cells with stolen neuronal mitochondria could establish more metastatic colonies.⁷ Stopping this theft could help halt breast cancer’s spread.

“This paper is pretty transformative,” said Jonathan Brestoff, a mitochondria biologist at Washington University in St. Louis who was not involved in the study. “No one had ever shown mitochondrial transfer from neuronal cells or established any functional consequence from this. They made an amazing finding!”

Ayala has studied the interplay between cancer cells and neurons for over two decades.⁸ In a 2001 study, he and his colleagues showed that mouse neurons developed more projections when researchers co-cultured them with a human prostate cancer cell line compared to when they grew them alone.⁹ Since then, Ayala’s team, as well as other researchers, have increasingly reported cancer’s dependence on the nervous system and indicated that metabolic reprogramming might be at the heart of that relationship.^10-14

“We saw that denervation affected cancer metabolism, and for many, many years, I tried to find how that happened,” Ayala said. “Now, we’re finally lucky enough to find out.”

The partnership that led to this new discovery began when Ayala reached out to Grelet in 2023 to congratulate him on a paper where his team had developed a CRISPR-based method to characterize how cancer cells affect neuronal differentiation in a co-culture model.¹⁵ Their email correspondence was the start of what Ayala described as “two incredible years of collaboration.”

Ayala said, “Simon showed me his mitochondrial transfer data, and I said, ‘Simon, I have some 15-year-old transcriptomics and metabolomics data in breast cancer that I never published. Let’s put things together.’”

For the study, Ayala, Grelet, and their team developed a genetic reporter system called MitoTRACER that could permanently label cancer cells that ever robbed mitochondria. In this approach, the researchers engineered breast cancer cells to constitutively express a red fluorophore that would switch to green in the presence of a Cre recombinase enzyme. They anchored Cre to the mitochondria of the co-cultured neurons so that the enzyme would be delivered upon nerve-to-tumor mitochondrial transfer. Thus, cancer cells that had gotten mitochondria from neurons would fluoresce green, while those that hadn’t stayed red. The researchers could separate the cells using fluorescence-activated cell sorting (FACS).

Then, the researchers compared breast cancer cells that had stolen mitochondria from neurons to the ones that hadn’t using various biochemical assays. They found that the cancer cells that had stolen neuronal mitochondria had significantly higher ATP content, lower oxidative stress, and higher resistance to shear stress—all of which have been linked to cancer’s metastatic capacity.^16-18

To investigate the relevance of their findings in vivo, the researchers transplanted MitoTRACER-labeled co-cultures of nerve and cancer cells into mice mammary fat pads. They found that in the primary breast tumor, only 5.4 percent of cells had neuronal mitochondria, whereas in the lung and brain, the proportions were as high as 27.3 percent and 46 percent, respectively.

“I didn’t expect the metastasis data to be so clean,” Ayala said. “Biology is usually complicated, and it’s often difficult to find a straightforward story. But this time, it was very, very clear.”