Many cancers are innervated, and cancer-infiltrating neurons have been linked to higher cancer aggressiveness and metastatic potential. However, the underlying mechanisms are still unknown. A new study using mouse models of breast cancer reports that cancer-associated neurons enhance cancer cell metabolic capacity and metastatic dissemination by transferring their mitochondria. Hoover and colleagues first showed that neurotoxin-mediated denervation in a human ductal carcinoma in situ xenograft model reduced the incidence of invasive lesions compared to control mice. Then the researchers labeled the mitochondria of host mammary fat pad neurons using a lentiviral construct to induce GFP protein expression, before injecting 4T1 breast cancer cells into the fat pad. Flow cytometry analysis confirmed the presence of tumor cells exhibiting the green signal, consistent with a nerve-to-cancer transfer of mitochondria. Finally, the team developed MitoTRACER, a reporter of cell-to-cell mitochondrial transfer based on cre-lox recombination that permanently labels recipient cancer cells and their progeny. The fate mapping experiment revealed enrichment of mitochondria-recipient cancer cells or their progeny at metastatic tumor sites, indicating higher metastatic potential. These findings could guide the development of therapeutic strategies targeting nerve–cancer mitochondrial transfers to prevent metastatic disease.
Original reference: Hoover, G. et al. Nature https://doi.org/10.1038/s41586-025-09176-8 (2025)
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