Nerve-to-Cancer Transfer of Mitochondria During Cancer Metastasis

Authors

Gregory Hoover
Shila Gilbert
Olivia Curley
Clémence Obellianne
Mike T Lin
William Hixson
Terry W Pierce
Joel F Andrews
Mikhail F Alexeyev
Yi Ding
Ping Bu
Fariba Behbod
Daniel Medina
Jeffrey T Chang
Gustavo Ayala
Simon Grelet

Language

English

Publication Date

8-1-2025

Journal

Nature

DOI

10.1038/s41586-025-09176-8

PMID

40562940

PMCID

PMC12328229

PubMedCentral® Posted Date

6-25-2025

PubMedCentral® Full Text Version

Post-print

Abstract

The nervous system has a pivotal role in cancer biology, and pathological investigations have linked intratumoural nerve density to metastasis1. However, the precise impact of cancer-associated neurons and the communication channels at the nerve–cancer interface remain poorly understood. Previous cancer denervation models in rodents and humans have highlighted robust cancer dependency on nerves, but the underlying mechanisms that drive nerve-mediated cancer aggressivity remain unknown2,3. Here we show that cancer-associated neurons enhance cancer metabolic plasticity by transferring mitochondria to cancer cells. Breast cancer denervation and nerve–cancer coculture models confirmed that neurons significantly improve tumour energetics. Neurons cocultured with cancer cells undergo metabolic reprogramming, resulting in increased mitochondrial mass and subsequent transfer of mitochondria to adjacent cancer cells. To precisely track the fate of recipient cells, we developed MitoTRACER, a reporter of cell-to-cell mitochondrial transfer that permanently labels recipient cancer cells and their progeny. Lineage tracing and fate mapping of cancer cells acquiring neuronal mitochondria in primary tumours revealed their selective enrichment at metastatic sites following dissemination. Collectively, our data highlight the enhanced metastatic capabilities of cancer cells that receive mitochondria from neurons in primary tumours, shedding new light on how the nervous system supports cancer metabolism and metastatic dissemination.

Keywords

Mitochondria, Animals, Neoplasm Metastasis, Mice, Neurons, Female, Humans, Breast Neoplasms, Cell Line, Tumor, Coculture Techniques, Energy Metabolism, Cell Lineage, Cell Communication, Breast cancer, Mechanisms of disease, Cancer microenvironment

Published Open-Access

yes

Recommended Citation

Hoover, Gregory; Gilbert, Shila; Curley, Olivia; et al., "Nerve-to-Cancer Transfer of Mitochondria During Cancer Metastasis" (2025). Faculty and Staff Publications. 4994.
https://digitalcommons.library.tmc.edu/baylor_docs/4994