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’Neill

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)303-313
Number of pages11
JournalJOURNAL OF NEURO-ONCOLOGY
Volume141
Issue number2
DOIs
Publication statusPublished - Jan 2019
Externally publishedYes

Keywords

  • Brain tumour
  • Glioma
  • Invasion
  • Mechanobiology
  • Tropomyosin

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    Mitchell, C. B., Black, B., Sun, F., Chrzanowski, W., Cooper-White, J., Maisonneuve, B., Stringer, B., Day, B., Biro, M., & O’Neill, G. M. (2019). Tropomyosin Tpm 2.1 loss induces glioblastoma spreading in soft brain-like environments. JOURNAL OF NEURO-ONCOLOGY, 141(2), 303-313. https://doi.org/10.1007/s11060-018-03049-z