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E-GEOD-76842 - Suppression of type I interferon signaling overcomes the oncogene-induced senescence and mediates melanoma development and progression

Status
Released on 14 January 2016, last updated on 15 January 2016
Organism
Mus musculus
Samples (8)
Array (1)
Protocols (7)
Description
Activation of oncogenes often leads to induction of the DNA damage responses and onset of the cell senescence. Given that DNA damage can also trigger production of type I interferons (IFN) that contribute to senescence development, we sought to determine the role of IFN in the oncogene-induced senescence. Our data in mouse model demonstrate that inactivation of IFN signaling is sufficient for inducing melanomas in melanocytes harboring mutant Braf. Restoration of IFN signaling in IFN-deficient melanoma cells induces cell senescence and suppresses melanoma progression. In addition, data in human patients that received high dose IFN therapy and in mouse transplanted tumor models strongly suggest the importance of the non-cell-autonomous IFN signaling. Suppression of IFN signaling mediated by the downregulation of IFN receptor IFNAR1 invariably occurs during development of mouse melanoma. Mice harboring the IFNAR1 mutant, which is relatively resistant to downregulation, delay melanoma development, suppress the metastatic disease, and better respond to treatment with BRAF or PD1 inhibitors. These results suggest that IFN signaling is an important tumor suppressive pathway that inhibits melanoma development and progression. Accordingly, the inhibition of IFN pathway via IFNAR1 downregulation plays a key role in melanoma pathogenesis. Conversely, these data also argue for targeting IFNAR1 downregulation to prevent the metastatic disease and improve the efficacy of molecularly targeted and immune-targeted therapies. Two genotypes of mice were examined at 2 to 3 times after tamoxifen adminstration, with 2 replicates for each condition, yielding 8 samples in total.
Experiment type
transcription profiling by array 
Contacts
daniel beiting <beiting@vet.upenn.edu>, Daniel Beiting, Kanstantsin Katlinski, Serge Fuchs, Yuliya Katlinskaya
MIAME
PlatformsProtocolsVariablesProcessedRaw
Files
Investigation descriptionE-GEOD-76842.idf.txt
Sample and data relationshipE-GEOD-76842.sdrf.txt
Processed data (1)E-GEOD-76842.processed.1.zip
Additional data (1)E-GEOD-76842.additional.1.zip
Array designA-MEXP-1174.adf.txt
Links