Cytoplasmic Cyclin D1 regulates glioblastoma dissemination
Guasch Vallés, Marta
Santacana Espasa, Maria
Gatius Calderó, Sònia
Schuhmacher, Alberto J.
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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.
Is part ofJournal of Pathology, 2019, vol. 248, núm. 4, p. 501-513
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