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IER2-induced senescence drives melanoma invasion through osteopontin

Kyjacova, L.; Saup, R.; Rönsch, K.; Wallbaum, S.; Dukowic-Schulze, S.; Foss, A.; Scherer, S. D.; Rothley, M.; Neeb, A.; Grau, N.; Thiele, W.; Thaler, S.; Cremers, N.; Sticht, C.; Gretz, N.; Garvalov, B. K.; Utikal, J.; Sleeman, J. P.

Abstract:
Expression of the immediate-early response gene IER2 has been associated with the progression of several types of cancer, but its functional role is poorly understood. We found that increased IER2 expression in human melanoma is associated with shorter overall survival, and subsequently investigated the mechanisms through which IER2 exerts this effect. In experimental melanoma models, sustained expression of IER2 induced senescence in a subset of melanoma cells in a p53/MAPK/AKT-dependent manner. The senescent cells produced a characteristic secretome that included high levels of the extracellular phosphoglycoprotein osteopontin. Nuclear localization of the IER2 protein was critical for both the induction of senescence and osteopontin secretion. Osteopontin secreted by IER2-expressing senescent cells strongly stimulated the migration and invasion of non-senescent melanoma cells. Consistently, we observed coordinate expression of IER2, p53/p21, and osteopontin in primary human melanomas and metastases, highlighting the pathophysiological relevance of IER2-mediated senescence in melanoma progression. Together, our study reveals that sustained IER2 expression drives melanoma invasion and progression through stimulating osteopontin secretion via the stochastic induction of senescence.


Verlagsausgabe §
DOI: 10.5445/IR/1000139191
Veröffentlicht am 20.10.2021
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Biologische und Chemische Systeme (IBCS)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2021
Sprache Englisch
Identifikator ISSN: 0950-9232, 1476-5594
KITopen-ID: 1000139191
HGF-Programm 47.14.02 (POF IV, LK 01) Information Storage and Processing in the Cell Nucleus
Erschienen in Oncogene
Verlag Springer Nature [academic journals on nature.com]
Vorab online veröffentlicht am 05.10.2021
Nachgewiesen in Web of Science
Scopus
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