Suppression of Type I Interferon Signaling Overcomes Oncogene-Induced Senescence and Mediates Melanoma Development and Progression. Cell Rep 2016 Apr 05;15(1):171-180
Date
04/08/2016Pubmed ID
27052162Pubmed Central ID
PMC4826807DOI
10.1016/j.celrep.2016.03.006Scopus ID
2-s2.0-84963545903 (requires institutional sign-in at Scopus site) 90 CitationsAbstract
Oncogene activation induces DNA damage responses and cell senescence. We report a key role of type I interferons (IFNs) in oncogene-induced senescence. IFN signaling-deficient melanocytes expressing activated Braf do not exhibit senescence and develop aggressive melanomas. Restoration of IFN signaling in IFN-deficient melanoma cells induces senescence and suppresses melanoma progression. Additional data from human melanoma patients and mouse transplanted tumor models suggest the importance of non-cell-autonomous IFN signaling. Inactivation of the IFN pathway is mediated by the IFN receptor IFNAR1 downregulation that invariably occurs during melanoma development. Mice harboring an IFNAR1 mutant, which is partially resistant to downregulation, delay melanoma development, suppress metastatic disease, and better respond to BRAF or PD-1 inhibitors. These results suggest that IFN signaling is an important tumor-suppressive pathway that inhibits melanoma development and progression and argue for targeting IFNAR1 downregulation to prevent metastatic disease and improve the efficacy of molecularly target and immune-targeted melanoma therapies.
Author List
Katlinskaya YV, Katlinski KV, Yu Q, Ortiz A, Beiting DP, Brice A, Davar D, Sanders C, Kirkwood JM, Rui H, Xu X, Koumenis C, Diehl JA, Fuchs SYMESH terms used to index this publication - Major topics in bold
AdultAged
Aged, 80 and over
Animals
Cell Line, Tumor
Cellular Senescence
Down-Regulation
Female
HEK293 Cells
Humans
Interferon Type I
Male
Melanocytes
Melanoma
Mice
Mice, Inbred C57BL
Middle Aged
Mutation
Proto-Oncogene Proteins B-raf
Receptor, Interferon alpha-beta
Signal Transduction
