Cytoplasmic Cyclin D1 regulates glioblastoma dissemination

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

doi:https://doi.org/10.1002/path.5277

View/Open

028538.pdf (4.163Mb)

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.

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

Is part of

Journal of Pathology, 2019, vol. 248, núm. 4, p. 501-513