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

Cancer Cell. 2019 Jan 14;35(1):33-45.e6. doi: 10.1016/j.ccell.2018.12.001.

Abstract

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.

Keywords: 25-hydroxycholesterol; IFNAR1; adjuvant therapy; exosomes; extracellular vesicles; interferon; melanoma; metastasis; pre-metastatic niche; reserpine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Disease Progression
  • Extracellular Vesicles / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockout Techniques
  • Humans
  • Interferons / pharmacology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary*
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Mice
  • Neoplasm Metastasis
  • Oxysterols / metabolism
  • Receptor, Interferon alpha-beta / metabolism*
  • Reserpine / administration & dosage
  • Reserpine / pharmacology
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism*
  • THP-1 Cells

Substances

  • IFNAR2 protein, human
  • Oxysterols
  • Receptor, Interferon alpha-beta
  • Reserpine
  • Interferons
  • Steroid Hydroxylases
  • cholesterol 25-hydroxylase