An Interferon-Driven Oxysterol-Based Defense against Tumor-Derived Extracellular Vesicles

Tumor-derived extracellular vesicles (TEV) “educate” healthy cells to promote metastases. We found that melanoma TEV downregulated type I interferon (IFN) receptor and expression of IFN-inducible cholesterol 25-hydroxylase (CH25H). CH25H produces 25-hydroxycholesterol, which inhibited TEV uptake. Low CH25H levels in leukocytes from melanoma patients correlated with poor prognosis. Mice incapable of downregulating the IFN receptor and Ch25h were resistant to TEV uptake, TEV-induced pre-metastatic niche, and melanoma lung metastases; however, ablation of Ch25h reversed these phenotypes. An anti-hypertensive drug, reserpine, suppressed TEV uptake and disrupted TEV-induced formation of the pre-metastatic niche and melanoma lung metastases. These results suggest the importance of CH25H in defense against education of normal cells by TEV and argue for the use of reserpine in adjuvant melanoma therapy. [Display omitted] •Tumor-derived extracellular vesicles (TEV) downregulate IFNAR1 and CH25H•CH25H acts to restrict TEV uptake and limit the education of healthy cells•Downregulation of CH25H in normal cells promotes melanoma metastasis•Disruption of TEV uptake and education by reserpine elicits anti-metastatic effects Ortiz et al. reveal that melanoma-derived extracellular vesicles (EV) downregulate type I interferon receptor (IFNAR1) and cholesterol 25-hydroxylase (CH25H) in normal cells to facilitate EV uptake and pre-metastatic niche development. IFNAR1-CH25H upregulation or reserpine treatment inhibits EV uptake and metastasis.