title: Suppression of Type I Interferon Signaling Overcomes Oncogene-Induced Senescence and Mediates Melanoma Development and Progression.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Yuliya V
authors.initials: YV
authors.lastname: Katlinskaya
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kanstantsin V
authors.initials: KV
authors.lastname: Katlinski
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Qiujing
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Angelica
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Beiting
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Brice
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.
authors.forename: Diwakar
authors.initials: D
authors.lastname: Davar
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Sanders
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.affiliation: Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
authors.affiliation: Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: syfuchs@vet.upenn.edu.
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D015536:Down-Regulation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D008297:Male; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; interferon receptor; melanoma; metastasis; senescence; type I interferon