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Tumor-derived miR-9-5p-loaded EVs regulate cholesterol homeostasis to promote breast cancer liver metastasis in mice
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Tumor-derived miR-9-5p-loaded EVs regulate cholesterol homeostasis to promote breast cancer liver metastasis in mice
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Journal Article
Tumor-derived miR-9-5p-loaded EVs regulate cholesterol homeostasis to promote breast cancer liver metastasis in mice
2024
Overview
Cancer cells secrete extracellular vesicles (EV) encapsulating bioactive cargoes to facilitate inter-organ communication in vivo and are emerging as critical mediators of tumor progression and metastasis, a condition which is often accompanied by a dysregulated cholesterol metabolism. Whether EVs are involved in the control of cholesterol homeostasis during tumor metastasis is still undefined and warrant further investigation. Here, we find that breast cancer-derived exosomal miR-9-5p induces the expression of HMGCR and CH25H, two enzymes involved in cholesterol synthesis and the conversion of 25-hydroxycholesterol from cholesterol by targeting INSIG1, INSIG2 and ATF3 genes in the liver. Notably, in vivo miR-9-5p antagomir treatment and genetic CH25H ablation prevents tumor metastasis in a mouse model of breast cancer. Thus, our findings reveal the regulatory mechanism of tumor-derived miR-9-5p in liver metastasis by linking oxysterol metabolism and Kupffer cell polarization, shedding light on future applications for cancer diagnosis and treatment.
Tumor-derived extracellular vesicles (EVs) critically regulate tumor development and progression. Here the authors show that, in a mouse model of breast cancer, miR-9-5p-loaded EVs promote cholesterol biosynthesis and conversion into the oncometabolite 25-hydroxycholesterol, favoring immune evasion and promoting liver metastasis.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/31
/ 14/19
/ 14/28
/ 38/23
/ 38/39
/ 38/5
/ 42
/ 45
/ 45/91
/ 49
/ 82/51
/ 82/58
/ 96
/ Ablation
/ Activating transcription factor 3
/ Animals
/ Breast Neoplasms - metabolism
/ Breast Neoplasms - pathology
/ Extracellular Vesicles - metabolism
/ Female
/ Gene Expression Regulation, Neoplastic
/ Humanities and Social Sciences
/ Humans
/ Hydroxycholesterols - metabolism
/ Hydroxymethylglutaryl CoA Reductases - genetics
/ Hydroxymethylglutaryl CoA Reductases - metabolism
/ Liver
/ Liver Neoplasms - metabolism
/ Membrane Proteins - genetics
/ Membrane Proteins - metabolism
/ Mice
/ Regulatory mechanisms (biology)
/ Science
/ Tumors
/ Vesicles
