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Journal of Neuro-Oncology

, Volume 141, Issue 2, pp 303–313 | Cite as

Tropomyosin Tpm 2.1 loss induces glioblastoma spreading in soft brain-like environments

  • Camilla B. Mitchell
  • Bronte Black
  • Faith Sun
  • Wojciech Chrzanowski
  • Justin Cooper-White
  • Benois Maisonneuve
  • Brett Stringer
  • Bryan Day
  • Maté Biro
  • Geraldine M. O’NeillEmail author
Laboratory Investigation

Abstract

Introduction

The brain is a very soft tissue. Glioblastoma (GBM) brain tumours are highly infiltrative into the surrounding healthy brain tissue and invasion mechanisms that have been defined using rigid substrates therefore may not apply to GBM dissemination. GBMs characteristically lose expression of the high molecular weight tropomyosins, a class of actin-associating proteins and essential regulators of the actin stress fibres and focal adhesions that underpin cell migration on rigid substrates.

Methods

Here, we investigated how loss of the high molecular weight tropomyosins affects GBM on soft matrices that recapitulate the biomechanical architecture of the brain.

Results

We find that Tpm 2.1 is down-regulated in GBM grown on soft substrates. We demonstrate that Tpm 2.1 depletion by siRNA induces cell spreading and elongation in soft 3D hydrogels, irrespective of matrix composition. Tpm 1.7, a second high molecular weight tropomyosin is also down-regulated when cells are cultured on soft brain-like surfaces and we show that effects of this isoform are matrix dependent, with Tpm 1.7 inducing cell rounding in 3D collagen gels. Finally, we show that the absence of Tpm 2.1 from primary patient-derived GBMs correlates with elongated, mesenchymal invasion.

Conclusions

We propose that Tpm 2.1 down-regulation facilitates GBM colonisation of the soft brain environment. This specialisation of the GBM actin cytoskeleton organisation that is highly suited to the soft brain-like environment may provide novel therapeutic targets for arresting GBM invasion.

Keywords

Brain tumour Glioma Mechanobiology Invasion Tropomyosin 

Notes

Acknowledgements

We thank Janine Woehlk, Dr Kylie Turner, Kaitlyn Griffin and Dr Peta Bradbury for technical assistance.

Funding

CM, BS, BD and GO are members of the Brain Cancer Discovery Collaborative, supported by the Cure Brain Cancer Foundation and the work was supported by a University of Sydney Strategic Priority Areas for Collaboration (SPARC) cancer grant to MB and GON.

Compliance with ethical standards

Conflict of interest

All authors declare no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Research involving human and animal participants

This article does not contain any studies with human participants.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Camilla B. Mitchell
    • 1
    • 11
  • Bronte Black
    • 1
  • Faith Sun
    • 1
  • Wojciech Chrzanowski
    • 2
    • 3
  • Justin Cooper-White
    • 4
    • 5
    • 6
  • Benois Maisonneuve
    • 6
  • Brett Stringer
    • 7
  • Bryan Day
    • 7
  • Maté Biro
    • 8
    • 9
  • Geraldine M. O’Neill
    • 1
    • 10
    Email author
  1. 1.Children’s Cancer Research Unit, Kids Research InstituteThe Children’s Hospital at WestmeadWestmeadAustralia
  2. 2.Faculty of PharmacyThe University of SydneySydneyAustralia
  3. 3.The University of Sydney Nano InstituteSydneyAustralia
  4. 4.Tissue Engineering and Microfluidics Group, Australian Institute for Bioengineering and NanotechnologyThe University of QueenslandBrisbaneAustralia
  5. 5.School of Chemical EngineeringThe University of QueenslandBrisbaneAustralia
  6. 6.CSIRO, Manufacturing Flagship, Biomedical Manufacturing ProgramClaytonAustralia
  7. 7.QIMR Berghofer Medical Research InstituteHerstonAustralia
  8. 8.EMBL Australia Single Molecule Science Node, School of Medical SciencesThe University of New South WalesSydneyAustralia
  9. 9.Centenary Institute, Sydney Medical SchoolThe University of SydneySydneyAustralia
  10. 10.Discipline of Childhood and Adolescent HealthThe University of SydneySydneyAustralia
  11. 11.Division of Cancer ResearchPeter MacCallum Cancer CentreMelbourneAustralia

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