Nerve-to-cancer transfer of mitochondria during cancer metastasis

• 成果类型: Article
• 署名作者: Hoover, Gregory; Gilbert, Shila; Curley, Olivia; Obellianne, Clemence; Lin, Mike T.; Hixson, William; Pierce, Terry W.; Andrews, Joel F.; Alexeyev, Mikhail F.; Ding, Yi; Bu, Ping; Behbod, Fariba; Medina, Daniel; Chang, Jeffrey T.; Ayala, Gustavo; Grelet, Simon
• 署名单位: University of South Alabama; University of South Alabama; University of South Alabama; University of South Alabama; University of Texas System; University of Texas Health Science Center Houston; University of Kansas; University of Kansas Medical Center; Baylor College of Medicine; University of Texas System; University of Texas Health Science Center Houston
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3297
• DOI: 10.1038/s41586-025-09176-8
• 发表日期: 2025-08-07
• 关键词: perineural invasion; oxidative stress; tumor; neurogenesis; regulator; prognosis; biomarker; rescue; cells; dna

摘要

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.