Abstract:
:Cellular senescence is a major barricade on the path of cancer development, yet proteins secreted from senescent cells exert complex and often discordant effects on subsequent cancer evolution. Somatic genome alternations driving the formation of nevi and melanoma are efficient inducers of cellular senescence. Melanocyte and melanoma cell senescence is likely to come into play as a key factor affecting the course of tumorigenesis and responsiveness to therapy; little mechanistic information has been generated, however, that substantiates this idea and facilitates its clinical translation. Here, we established and characterized a model of melanoma cell senescence in which pharmacologically induced DNA damage triggered divergent ATM kinase- and STING-dependent intracellular signaling cascades and resulted in cell cycle arrest, cytomorphologic remodeling, and drastic secretome changes. Targeted proteome profiling revealed that senescent melanoma cells in this model secreted a panoply of proteins shaping the tumor immune microenvironment. CRISPR-mediated genetic ablation of the p38α and IKKβ signaling modules downstream of the ATM kinase severed the link between DNA damage and this secretory phenotype without restoring proliferative capacity. A similar genetic dissection showed that loss of STING signaling prevented type I interferon induction in DNA-damaged melanoma cells but otherwise left the senescence-associated processes in our model intact. Actionable proteins secreted from senescent melanoma cells or involved in senescence-associated intracellular signaling hold potential as markers for melanoma characterization and targets for melanoma treatment.
journal_name
Melanoma Resjournal_title
Melanoma researchauthors
Chavanet A,Hill KR,Jiménez-Andrade Y,Choo MK,White K,Park JMdoi
10.1097/CMR.0000000000000671subject
Has Abstractpub_date
2020-08-01 00:00:00pages
336-347issue
4eissn
0960-8931issn
1473-5636pii
00008390-202008000-00002journal_volume
30pub_type
杂志文章abstract::Protein tyrosyl phosphorylation is an essential component in intracellular signalling, with diverse and crucial functions including mediation of cell proliferation, survival, death, differentiation, migration and attachment. It is regulated by the balance between the activities of protein tyrosine kinases (PTKs) and p...
journal_title:Melanoma research
pub_type: 杂志文章,评审
doi:10.1097/00008390-200010000-00001
更新日期:2000-10-01 00:00:00
abstract::Development of brain metastases despite extracerebral response to systemic immunotherapy is a common problem in melanoma patients. We have previously described a murine melanoma vaccine of interferon-gamma (IFNgamma)-treated, irradiated syngeneic B16/G3.12 and allogeneic (Cloudman) melanoma cells, plus the adjuvant DE...
journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/00008390-200108000-00002
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/00008390-199704000-00008
更新日期:1997-04-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/00008390-199802000-00002
更新日期:1998-02-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/CMR.0b013e32835861f6
更新日期:2012-10-01 00:00:00
abstract::The CD10 antigen is a neutral endopeptidase expressed by a variety of mesenchymal tumours (haemopoietic or not), including a subset of malignant melanomas. We investigated the expression of CD10 in formalin-fixed, paraffin-embedded tissue specimens of 72 cutaneous melanomas (28 primary, 26 metastatic to the skin and 1...
journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/00008390-200206000-00007
更新日期:2002-06-01 00:00:00
abstract::In patients with metastatic cancer, gut microbiome composition differs between responder and non-responders to immune checkpoint inhibitors. However, there is little consensus on the microbiome taxa associated with response or lack of response. Additionally, recognized confounders of gut microbiome composition have ge...
journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/CMR.0000000000000656
更新日期:2020-06-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/00008390-200012000-00010
更新日期:2000-12-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/CMR.0000000000000445
更新日期:2018-08-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/00008390-199406000-00003
更新日期:1994-06-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/CMR.0000000000000420
更新日期:2018-04-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/00008390-199211000-00002
更新日期:1992-11-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/CMR.0000000000000550
更新日期:2019-04-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/CMR.0b013e3283350554
更新日期:2010-04-01 00:00:00
abstract::The mechanism of selective incorporation of thiourea into melanotic melanoma was investigated by model experiments in which the effect of the compound was examined at various stages of melanogenesis in vitro. Up to 50% inhibition of dopachrome formation was observed in the tyrosinase-dopa reaction in the presence of t...
journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/00008390-199712000-00006
更新日期:1997-12-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/00008390-200110000-00012
更新日期:2001-10-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/CMR.0000000000000281
更新日期:2016-10-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/CMR.0b013e32830ce7d7
更新日期:2008-12-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/CMR.0000000000000330
更新日期:2017-06-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/CMR.0b013e32830b3536
更新日期:2008-10-01 00:00:00
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journal_title:Melanoma research
pub_type: 临床试验,杂志文章
doi:10.1097/00008390-199306000-00005
更新日期:1993-06-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/01.cmr.0000056259.56735.eb
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journal_title:Melanoma research
pub_type: 杂志文章,评审
doi:
更新日期:1991-11-01 00:00:00
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journal_title:Melanoma research
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1097/01.cmr.0000136707.60108.ab
更新日期:2004-08-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/CMR.0000000000000519
更新日期:2020-06-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/CMR.0000000000000579
更新日期:2020-04-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/CMR.0b013e328303beac
更新日期:2008-08-01 00:00:00
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journal_title:Melanoma research
pub_type: 共识发展会议,杂志文章,实务指引
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更新日期:2008-02-01 00:00:00
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/00008390-199504000-00009
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journal_title:Melanoma research
pub_type: 杂志文章
doi:10.1097/00008390-200304000-00009
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