Tumor-derived miR-9-5p-loaded EVs regulate cholesterol homeostasis to promote breast cancer liver metastasis in mice

Mei-Xin Li ¹, Sheng Hu ¹, He-Hua Lei ^2,3

¹Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, 430072, China.
²State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy of Precision Measurement Science and Technology, Chinese Academy of Sciences (CAS), Wuhan, Hubei, 430064, China.
³University of Chinese Academy of Sciences, 100864, Beijing, China.
⁴College of Biomedical Engineering and Instrument Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
⁵Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
⁶General Surgery, Ruijin Hospital & Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
⁷State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy of Precision Measurement Science and Technology, Chinese Academy of Sciences (CAS), Wuhan, Hubei, 430064, China. zhanglm@wipm.ac.cn.
⁸University of Chinese Academy of Sciences, 100864, Beijing, China. zhanglm@wipm.ac.cn.
⁹Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, 430072, China. weiyan@whu.edu.cn.

⁰Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, 430072, China.

Nature Communications +

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December 3, 2024

View abstract on PubMed

Summary

Breast cancer cells release microRNAs (miRNAs) in extracellular vesicles (EVs) that promote liver metastasis by altering cholesterol metabolism. Inhibiting these miRNAs or specific enzymes prevents metastasis in mice.

Area Of Science

Oncology
Molecular Biology
Metabolism

Background

Extracellular vesicles (EVs) mediate intercellular communication and are implicated in tumor progression and metastasis.
Tumor metastasis is often associated with dysregulated cholesterol metabolism, but the role of EVs in cholesterol homeostasis remains unclear.

Purpose Of The Study

To investigate the role of breast cancer-derived EVs in regulating cholesterol homeostasis during liver metastasis.
To identify specific molecular mechanisms by which EVs influence metastasis-associated metabolic changes.

Main Methods

Analysis of microRNA (miR-9-5p) content in breast cancer-derived exosomes.
In vitro studies targeting INSIG1, INSIG2, and ATF3 genes.
In vivo mouse models of breast cancer liver metastasis.
In vivo antagomir treatment and genetic ablation of CH25H.

Main Results

Breast cancer exosomal miR-9-5p upregulates HMGCR and CH25H liver enzymes by targeting INSIG1, INSIG2, and ATF3.
miR-9-5p promotes cholesterol synthesis and 25-hydroxycholesterol conversion.
In vivo inhibition of miR-9-5p or CH25H significantly reduced liver metastasis in mice.

Conclusions

Tumor-derived exosomal miR-9-5p plays a critical role in liver metastasis by modulating cholesterol metabolism and Kupffer cell polarization.
Targeting exosomal miRNAs and related metabolic pathways offers potential therapeutic strategies for preventing cancer metastasis.