Camilla B Mitchell1,2, Bronte Black1, Faith Sun1, Wojciech Chrzanowski3,4, Justin Cooper-White5,6,7, Benois Maisonneuve7, Brett Stringer8, Bryan Day8, Maté Biro9,10, Geraldine M O'Neill11,12. 1. Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia. 2. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. 3. Faculty of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia. 4. The University of Sydney Nano Institute, Sydney, NSW, 2006, Australia. 5. Tissue Engineering and Microfluidics Group, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, 4072, Australia. 6. School of Chemical Engineering, The University of Queensland, Brisbane, 4072, Australia. 7. CSIRO, Manufacturing Flagship, Biomedical Manufacturing Program, Clayton, VIC, Australia. 8. QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. 9. EMBL Australia Single Molecule Science Node, School of Medical Sciences, The University of New South Wales, Sydney, Australia. 10. Centenary Institute, Sydney Medical School, The University of Sydney, Sydney, Australia. 11. Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia. geraldine.oneill@health.nsw.gov.au. 12. Discipline of Childhood and Adolescent Health, The University of Sydney, Sydney, NSW, Australia. geraldine.oneill@health.nsw.gov.au.
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.
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.
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