Breast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis

作者：Xianhui Ruan, Wei Yan, Minghui Cao, Ray Anthony M. Daza, Miranda Fong, Kai-Fu Yang, Jun Wu, Xuxiang Liu, Melanie R. Palomares, Xiwei Wu, Arthur Li, Yuan Chen, Rahul Jandial, Nicholas C. Spitzer, Robert F. Hevner, Shizhen Emily Wang · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-48740-0 · 被引用次数：46 · 研究领域：Extracellular vesicles in disease、MicroRNA in disease regulation、Cancer-related molecular mechanisms research

Breast cancer metastasis to the brain is a clinical challenge rising in prevalence. However, the underlying mechanisms, especially how cancer cells adapt a distant brain niche to facilitate colonization, remain poorly understood. A unique metabolic feature of the brain is the coupling between neurons and astrocytes through glutamate, glutamine, and lactate. Here we show that extracellular vesicles from breast cancer cells with a high potential to develop brain metastases carry high levels of miR-199b-5p, which shows higher levels in the blood of breast cancer patients with brain metastases comparing to those with metastatic cancer in other organs. miR-199b-5p targets solute carrier transporters (SLC1A2/EAAT2 in astrocytes and SLC38A2/SNAT2 and SLC16A7/MCT2 in neurons) to hijack the neuron-astrocyte metabolic coupling, leading to extracellular retention of these metabolites and promoting cancer cell growth. Our findings reveal a mechanism through which cancer cells of a non-brain origin reprogram neural metabolism to fuel brain metastases.