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01-01-2020 | Glioblastoma | Original Paper

FOCAD loss impacts microtubule assembly, G2/M progression and patient survival in astrocytic gliomas

Authors: Frank Brand, Alisa Förster, Anne Christians, Martin Bucher, Carina M. Thomé, Marc S. Raab, Manfred Westphal, Torsten Pietsch, Andreas von Deimling, Guido Reifenberger, Peter Claus, Bettina Hentschel, Michael Weller, Ruthild G. Weber

Published in: Acta Neuropathologica | Issue 1/2020

Abstract

In search of novel genes associated with glioma pathogenesis, we have previously shown frequent deletions of the KIAA1797/FOCAD gene in malignant gliomas, and a tumor suppressor function of the encoded focadhesin impacting proliferation and migration of glioma cells in vitro and in vivo. Here, we examined an association of reduced FOCAD gene copy number with overall survival of patients with astrocytic gliomas, and addressed the molecular mechanisms that govern the suppressive effect of focadhesin on glioma growth. FOCAD loss was associated with inferior outcome in patients with isocitrate dehydrogenase 1 or 2 (IDH)-mutant astrocytic gliomas of WHO grades II–IV. Multivariate analysis considering age at diagnosis as well as IDH mutation, MGMT promoter methylation, and CDKN2A/B homozygous deletion status confirmed reduced FOCAD gene copy number as a prognostic factor for overall survival. Using a yeast two-hybrid screen and pull-down assays, tubulin beta-6 and other tubulin family members were identified as novel focadhesin-interacting partners. Tubulins and focadhesin co-localized to centrosomes where focadhesin was enriched in proximity to centrioles. Focadhesin was recruited to microtubules via its interaction partner SLAIN motif family member 2 and reduced microtubule assembly rates, possibly explaining the focadhesin-dependent decrease in cell migration. During the cell cycle, focadhesin levels peaked in G2/M phase and influenced time-dependent G2/M progression potentially via polo like kinase 1 phosphorylation, providing a possible explanation for focadhesin-dependent cell growth reduction. We conclude that FOCAD loss may promote biological aggressiveness and worsen clinical outcome of diffuse astrocytic gliomas by enhancing microtubule assembly and accelerating G2/M phase progression.

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Title: FOCAD loss impacts microtubule assembly, G2/M progression and patient survival in astrocytic gliomas
Authors: Frank Brand
Alisa Förster
Anne Christians
Martin Bucher
Carina M. Thomé
Marc S. Raab
Manfred Westphal
Torsten Pietsch
Andreas von Deimling
Guido Reifenberger
Peter Claus
Bettina Hentschel
Michael Weller
Ruthild G. Weber
Publication date: 01-01-2020
Publisher: Springer Berlin Heidelberg
Keywords: Glioblastoma
Astrocytoma
Glioma
Glioma
Astrocytoma
Glioblastoma
Astrocytoma
Glioblastoma
Glioma
Published in: Acta Neuropathologica / Issue 1/2020
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02067-z

At a glance: The STEP trials

Springer Medicine

FOCAD loss impacts microtubule assembly, G2/M progression and patient survival in astrocytic gliomas

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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