Nerve-to-cancer transfer of mitochondria during cancer metastasis

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 () and Simon Grelet ()
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Gregory Hoover: University of South Alabama
Shila Gilbert: University of South Alabama
Olivia Curley: University of South Alabama
Clémence Obellianne: University of South Alabama
Mike T. Lin: University of South Alabama
William Hixson: University of South Alabama
Terry W. Pierce: University of South Alabama
Joel F. Andrews: University of South Alabama
Mikhail F. Alexeyev: University of South Alabama
Yi Ding: McGovern School of Medicine
Ping Bu: McGovern School of Medicine
Fariba Behbod: University of Kansas Medical Center
Daniel Medina: Baylor College of Medicine
Jeffrey T. Chang: University of Texas Health Science Center at Houston
Gustavo Ayala: McGovern School of Medicine
Simon Grelet: University of South Alabama

Nature, 2025, vol. 644, issue 8075, 252-262

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09176-8

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