Tropomyosin Tpm 2.1 loss induces glioblastoma spreading in soft brain-like environments
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.
Here, we investigated how loss of the high molecular weight tropomyosins affects GBM on soft matrices that recapitulate the biomechanical architecture of the brain.
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.
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.
KeywordsBrain tumour Glioma Mechanobiology Invasion Tropomyosin
We thank Janine Woehlk, Dr Kylie Turner, Kaitlyn Griffin and Dr Peta Bradbury for technical assistance.
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.
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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