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

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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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Acknowledgements

The authors wish to thank Alexander Pfeifer, Institute of Pharmacology and Toxicology, University of Bonn Medical Center and University of Bonn, Bonn, Germany for providing the lentivector construct expressing FOCAD-GFP; Erich Nigg, Biozentrum, University of Basel, Switzerland for helpful scientific discussions; Rudolf Bauerfeind, Research Core Unit for Laser Microscopy, Hannover Medical School, Germany for technical support with regard to live-cell imaging experiments; and the Cell Sorting Core Facility, Hannover Medical School, Germany.

Funding

FB received a grant from the Hochschulinterne Leistungsförderung (HiLF) program at Hannover Medical School. The German Glioma Network was supported by the German Cancer Aid (Stiftung Deutsche Krebshilfe) from 2004 to 2012 (Grant No. 70-3163-Wi 3).

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Authors and Affiliations

  1. Department of Human Genetics OE 6300, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Frank Brand, Alisa Förster, Anne Christians, Martin Bucher & Ruthild G. Weber

  2. Neurology Clinic and National Center for Tumor Diseases, Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Carina M. Thomé

  3. Department of Internal Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany

    Marc S. Raab

  4. Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Marc S. Raab

  5. Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Manfred Westphal

  6. Department of Neuropathology, University of Bonn Medical School, Bonn, Germany

    Torsten Pietsch

  7. Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

    Andreas von Deimling

  8. Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Andreas von Deimling

  9. Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany

    Guido Reifenberger

  10. German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Guido Reifenberger

  11. Department of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany

    Peter Claus

  12. Center for Systems Neuroscience (ZSN), Hannover, Germany

    Peter Claus

  13. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany

    Bettina Hentschel

  14. Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland

    Michael Weller

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  1. Frank Brand
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  2. Alisa Förster
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  3. Anne Christians
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  6. Marc S. Raab
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  7. Manfred Westphal
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  8. Torsten Pietsch
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  9. Andreas von Deimling
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  10. Guido Reifenberger
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  11. Peter Claus
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  12. Bettina Hentschel
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  13. Michael Weller
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  14. Ruthild G. Weber
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Contributions

FB, AC, BH, MiW, and RGW designed research; FB, AF, AC, MB, and CMT performed research; MSR, MaW, TP, AvD, GR, and PC contributed materials, patient/tumor data and expertise; FB, AC, BH, and RGW analyzed data and made figures; FB, AC, BH, MiW, and RGW wrote the manuscript; all authors reviewed and revised the manuscript.

Corresponding author

Correspondence to Ruthild G. Weber.

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Conflict of interest

GR received research grants from Roche and Merck as well as honoraria for advisory board activities from AbbVie. All other authors report no conflict of interest.

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Manfred Westphal, Torsten Pietsch, Andreas von Deimling, Guido Reifenberger, Bettina Hentschel, and Michael Weller represent the German Glioma Network.

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Brand, F., Förster, A., Christians, A. et al. FOCAD loss impacts microtubule assembly, G2/M progression and patient survival in astrocytic gliomas. Acta Neuropathol 139, 175–192 (2020). https://doi.org/10.1007/s00401-019-02067-z

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