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

Xianhui Ruan, Wei Yan, Minghui Cao, Ray Anthony M. Daza, Miranda Y. Fong, Kaifu Yang, Jun Wu, Xuxiang Liu, Melanie Palomares, Xiwei Wu, Arthur Li, Yuan Chen, Rahul Jandial, Nicholas C. Spitzer, Robert F. Hevner and Shizhen Emily Wang ()
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Xianhui Ruan: University of California San Diego
Wei Yan: University of California San Diego
Minghui Cao: University of California San Diego
Ray Anthony M. Daza: University of California San Diego
Miranda Y. Fong: University of California San Diego
Kaifu Yang: University of California San Diego
Jun Wu: City of Hope Beckman Research Institute
Xuxiang Liu: City of Hope Beckman Research Institute
Melanie Palomares: Cancer Prevention Movement
Xiwei Wu: City of Hope Beckman Research Institute
Arthur Li: City of Hope Beckman Research Institute
Yuan Chen: University of California San Diego
Rahul Jandial: Department of Surgery; City of Hope
Nicholas C. Spitzer: University of California San Diego
Robert F. Hevner: University of California San Diego
Shizhen Emily Wang: University of California San Diego

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-48740-0

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