Neurons as Charging Stations to Fuel Tumor Metastasis (Read the scientific version)

The New Study

Tumors are known to be extensively innervated. Tumor cells produce a variety of neurotropic factors to attract neuronal differentiation. Why do they do this? Previous studies revealed that tumor cells use sensory neurons to suppress immune responses from CD8+ T cells.¹ In a new study, Hoover and colleagues identify a previously unknown reason for this close association. They discovered that tumor cells steal neuronal mitochondria to enhance survival, promote growth, evade the immune system, and, most importantly, help in metastasis.²

Visualizing Mitochondrial Transfer

To confirm mitochondrial transfer from neurons to tumor cells, researchers used in vitro techniques and fluorescent labeling to distinguish different cell types. They genetically engineered neuronal cells to express enhanced green fluorescent protein (eGFP)-labeled mitochondria. Co-culturing these labeled neurons with tumor cells and analyzing them under a microscope revealed mitochondria transfer via nanotube-like structures. (Fig. 1).

Fig 1: Transfer of neuronal mitochondria from neurons (green) to tumor cells (red).

Transferred Mitochondria are Functional

After visualizing the transfer of mitochondria, researchers wanted to confirm that these organelles were indeed used by tumor cells for metabolic reprogramming. To do this, they used ρ⁰ 4T1 cells (which lack mitochondrial DNA and rely on external uridine to grow). These dysfunctional tumor cells were cocultured with ρ⁺ SVZ neural stem cells, which have healthy mitochondria.

After five days of coculture with neurons, tumor cells received mitochondria from neurons, confirming previous observations. However, the new functional transferred mitochondria allowed certain subsets of tumor cells to survive without uridine. This confirmed that the transferred mitochondria were functional in the recipient tumor cells.

Confirmation in Preclinical and Clinical Models

Clinical model: After establishing mitochondrial transfer in a simplified in vitro setup, researchers then analyzed whether similar findings were observed in clinical models. To do this, they examined prostate tissue from patients who underwent chemical denervation with botulinum toxin type A. This revealed that cancer cells from the denervated side of the prostate had a lower mitochondrial load than those on the saline-injected side.

Mito-TRACER: Experiments similar to the in vitro model using genetically labeled mitochondria in a xenograft mouse model further confirmed the transfer hypothesis. However, this method did not allow for permanent and long-term tracking. To address this issue, researchers developed a novel permanent genetic labeling strategy called Mito-TRACER.

In this method, recipient tumor cells were made to constitutively express the Ds-Red marker until they received neuronal mitochondria. Upon uptake of neuronal mitochondria, these red cells immediately switched to expressing eGFP and turned green. Time-lapse microscopy revealed a red-to-green switch in tumor cells that received mitochondria from neurons through nanotube-like structures.

Role in Metastasis

Researchers then used the Mito-TRACER method in a mouse model of metastatic breast cancer. They observed that switched tumor cells- the ones that turned green after receiving neuronal mitochondria- no longer stayed in the primary tumor. Most of these cells were found in the brain and lung tissue after metastasis.

Conclusion

This was the first study to shed light on a potential explanation for the close relationship between tumors and neurons. It involves metabolic reprogramming through the transfer of mitochondria from neurons to tumor cells. The transferred mitochondria provide tumor cells with extra energy to survive, grow, and metastasize to distant organs, especially the brain. This study also offers scientists a new target to inhibit tumor growth and metastasis.

References

1.          Balood, M. et al. Nociceptor neurons affect cancer immunosurveillance. Nature 611, 405–412 (2022).

2.          Hoover, G. et al. Nerve-to-cancer transfer of mitochondria during cancer metastasis. Nature 1–11 (2025) doi:10.1038/s41586-025-09176-8.