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

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.

• Authors: Angelica Ortiz, Jun Gui, Farima Zahedi, Pengfei Yu, Christina Cho, Sabyasachi Bhattacharya, Christopher J Carbone, Qiujing Yu, Kanstantsin V Katlinski, Yuliya V Katlinskaya, Simran Handa, Victor Haas, Susan W Volk, Angela K Brice, Kim Wals, Nicholas J Matheson, Robin Antrobus, Sonja Ludwig, Theresa L Whiteside, Cindy Sander, Ahmad A Tarhini, John M Kirkwood, Paul J Lehner, Wei Guo, Hallgeir Rui, Andy J Minn, Constantinos Koumenis, J Alan Diehl, Serge Y Fuchs
• Journal: Cancer cell (Cancer Cell) Vol. 35 Issue 1 Pg. 33-45.e6 (01 14 2019) ISSN: 1878-3686 [Electronic] United States
• PMID: 30645975 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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