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Cytoplasmic Cyclin D1 regulates glioblastoma dissemination

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Issue date
2019
Author
Cemeli, Tània
Guasch Vallés, Marta
Nàger Grifo, Mireia
Felip, Isidre
Cambray Carner, Serafí
Santacana Espasa, Maria
Gatius Calderó, Sònia
Pedraza González, Neus
Dolcet Roca, Xavier
Ferrezuelo, Francisco
Schuhmacher, Alberto J.
Herreros Danés, Judit
Garí Marsol, Eloi
Suggested citation
Cemeli, Tània; Guasch Vallés, Marta; Nàger Grifo, Mireia; Felip, Isidre; Cambray Carner, Serafí; Santacana Espasa, Maria; ... Garí Marsol, Eloi. (2019) . Cytoplasmic Cyclin D1 regulates glioblastoma dissemination. Journal of Pathology, 2019, vol. 248, núm. 4, p. 501-513. https://doi.org/10.1002/path.5277.
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Abstract
Glioblastoma (GBM) is a highly invasive brain neoplasia with an elevated recurrence rate after surgical resection. The CyclinD1 (Ccnd1)/Cdk4-RB1 axis is frequently altered in GBM, leading to over-proliferation by RB1 deletion or by Ccnd1/Cdk4 over-activation. By not so well understood mechanisms, high levels of Ccnd1-Cdk4 also promote GBM cell invasion. The purpose of this work is to elucidate the in vivo role of cytoplasmic Ccnd1-Cdk4 activity in the dissemination of GBM. We show that Ccnd1 activates invasion of primary human GBM cells through cytoplasmic RB1-independent mechanisms. By using GBM mouse models, we observed that evaded GBM cells showed cytoplasmic Ccnd1 co-localizing with regulators of cell invasion such as RalA and Paxillin. Our genetic data strongly suggest that, in GBM cells, the Ccnd1/Cdk4 complex is acting upstream of those regulators. Accordingly, expression of Ccnd1 induces FAK, RalA and Rac1 activities. Finally, in vivo experiments demonstrated increased GBM dissemination after expression of membrane-targeted Ccnd1. We conclude that Ccnd1-Cdk4 activity promotes GBM dissemination through cytoplasmic and RB1-independent mechanisms. Therefore, inhibition of Ccnd1-Cdk4 activity may be useful to hinder dissemination of recurrent GBM.
URI
http://hdl.handle.net/10459.1/67684
DOI
https://doi.org/10.1002/path.5277
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Journal of Pathology, 2019, vol. 248, núm. 4, p. 501-513
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  • Articles publicats (Ciències Mèdiques Bàsiques) [474]

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