Scientists have discovered that cancer cells recruit fibroblasts to support tumor growth by transferring mitochondria into them. Blocking this process might be a new way to fight the deadly disease [1].
It goes both ways
Cancer doesn’t act alone. Its success often hinges on recruiting neighboring cells into cooperation with cancer cells. Sometimes, those neighboring cells donate mitochondria to cancer cells [2], boosting the latter’s metabolism and promoting tumor growth.
In skin cancer, for instance, mitochondrial transfers from cancer-associated fibroblasts (CAFs) to cancer cells have been documented. Now, for the first time, a team of researchers from ETH Zurich has demonstrated that the opposite phenomenon also takes place: the transfer of mitochondria from cancer cells to CAFs.
CAFs are a key component of the tumor microenvironment [3]. They build and maintain the tumor’s support system by laying down stiff extracellular matrix (ECM), secreting growth factors and inflammatory signals, reshaping metabolism, promoting blood vessel growth (angiogenesis), and dampening immune responses.
Supercharging and reprogramming the fibroblasts
In their paper published in Nature Cancer, the researchers describe co-culturing highly malignant A431 skin cancer cells with human primary fibroblasts (HPF). By labeling mitochondria in the cancer cells, they were able to confirm that some of them ended up in the fibroblasts.
Mitochondrial transfer is a widespread phenomenon, such as in injury healing, and it can happen in several ways. However, the researchers were able to rule out all but one method: transfer via tunneling nanotubes (TNTs), thin, actin-based membrane bridges that directly ferry organelles and signals between cells. Using a drug that disrupts the formation of actin filaments strongly inhibited the transfer.
These results suggested that cancer cells extend TNTs to physically deliver their mitochondria directly into fibroblasts. The team also confirmed this phenomenon wasn’t unique to skin cancer, as they observed the same transfer happening with breast and pancreatic cancer cells.
Why would cancer cells transfer valuable mitochondria to other cells? As the researchers found, in HPFs that received mitochondria from cancer cells, several genes related to CAF phenotypes and ECM building were upregulated, and proliferation got a boost. Basically, it looked like mitochondrial transfer from cancer cells caused HPF reprogramming toward CAFs.
“Cancer cells actually exploit a mechanism for their own purposes that is beneficial in the event of injury. This allows them to grow into malignant tumors,” said cell biology professor Sabine Werner, a co-lead author of the study.
Assays showed increased oxidative phosphorylation and proton leak in recipient HPFs, which indicates that the cell’s energy-producing machinery is working overtime. Treatment with oligomycin, which impedes energy production by mitochondria, blocked both CAF marker induction and proliferation.
To prove that the mitochondria alone were responsible for this transformation, the scientists isolated mitochondria directly from cancer cells and transplanted them into normal fibroblasts. This was sufficient to induce the same CAF-like changes, confirming that the transferred mitochondria are the primary drivers of this reprogramming.
Crucially, not just any mitochondria would do. Mitochondria from non-cancerous cells had little effect, whereas mitochondria from more malignant cancer cells had a stronger effect. When dysfunctional mitochondria were transferred (from cancer cells with depleted mitochondrial DNA), the fibroblasts were not reprogrammed and did not support tumor growth in mice.
The master regulator of the transfer
In vivo, co-injecting A431 cells with fibroblasts that had received A431 mitochondria yielded bigger tumors and increased angiogenesis. That in-vivo impact raised the question of what tumor factor controls the handoff.
By analyzing gene expression data from human skin cancers, the team zeroed in on several genes involved in mitochondrial trafficking. One protein stood out: MIRO2, which was significantly overexpressed in cancer cells, particularly at the invasive edges of tumors where they interact with fibroblasts.
MIRO2 acts like a molecular motor, linking mitochondria to the cell’s transport network to control their position. The team hypothesized that cancer cells hijack MIRO2 to move their mitochondria out for delivery.
When RNA interference was used to reduce MIRO2 levels in cancer cells, the cells’ mitochondria clustered around the nucleus instead of spreading out. This reduced the cells’ ability to transfer mitochondria to fibroblasts and to convert them into CAFs. Conversely, increasing MIRO2 levels in cancer cells boosted their mitochondrial transfer activity.
“This protein is produced in very high quantities in cancer cells that transfer their mitochondria,” Werner mentioned.
When researchers injected cancer cells with depleted MIRO2 into mice, the cells failed to form tumors. However, when those MIRO2-deficient cells were coinjected with fibroblasts that had been pre-loaded with cancer mitochondria, this combination did induce tumor growth, suggesting that MIRO2’s role was to cause fibroblasts’ reprogramming into CAFs, and that that role was crucial for cancer development.
“The MIRO2 blockade worked in the test tube and in mouse models. “Whether it also works in human tissue remains to be seen,” said Werner. “If successful, such an inhibitor could be transferred to clinical applications in the longer term.”
Literature
[1] Cangkrama, M., Liu, H., Wu, X., Yates, J., Whipman, J., Gäbelein, C. G., … & Werner, S. (2025). MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation. Nature Cancer, 1-20.
[2] Zampieri, L. X., Silva-Almeida, C., Rondeau, J. D., & Sonveaux, P. (2021). Mitochondrial transfer in cancer: a comprehensive review. International journal of molecular sciences, 22(6), 3245.
[3] Sahai, E., Astsaturov, I., Cukierman, E., DeNardo, D. G., Egeblad, M., Evans, R. M., … & Werb, Z. (2020). A framework for advancing our understanding of cancer-associated fibroblasts. Nature Reviews Cancer, 20(3), 174-186.
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