Nerve-to-cancer transfer of mitochondria during cancer metastasis

  • Nature. 2025 Aug;644(8075):252-262. doi: 10.1038/s41586-025-09176-8.
Gregory Hoover  1  2 ,  Shila Gilbert  1  2 ,  Olivia Curley  1  2 ,  Clémence Obellianne  3 ,  Mike T Lin  4 ,  William Hixson  1  2 ,  Terry W Pierce  2 ,  Joel F Andrews  1  2 ,  Mikhail F Alexeyev  4 ,  Yi Ding  5 ,  Ping Bu  5 ,  Fariba Behbod  6 ,  Daniel Medina  7 ,  Jeffrey T Chang  8 ,  Gustavo Ayala  9 ,  Simon Grelet  10  11
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, Frederick P. Whiddon College of Medicine, University of South Alabama, Mobile, AL, USA.
  • 2. Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
  • 3. Department of Microbiology and Immunology, Frederick P. Whiddon College of Medicine, University of South Alabama, Mobile, AL, USA.
  • 4. Department of Physiology and Cell Biology, Frederick P. Whiddon College of Medicine, University of South Alabama, Mobile, AL, USA.
  • 5. Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston, McGovern School of Medicine, Houston, TX, USA.
  • 6. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
  • 7. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 8. Department of Integrative Biology & Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 9. Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston, McGovern School of Medicine, Houston, TX, USA. [email protected].
  • 10. Department of Biochemistry and Molecular Biology, Frederick P. Whiddon College of Medicine, University of South Alabama, Mobile, AL, USA. [email protected].
  • 11. Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA. [email protected].
PMID: 40562940 DOI: 10.1038/s41586-025-09176-8
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.