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

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. Breast cancer metastasis to the brain is rising in prevalence and is an increasingly lethal threat to the patients. Here, the authors show miR-199b-5p, secreted by some breast cancer cells and detected at a higher level in patients with brain metastases, impairs the metabolic coupling between neurons and astrocytes to facilitate development of brain metastasis.