Specialisation of the glioma cytoskeleton for navigating the soft tissue environment of the brain

O'Neill GM1,2

  1. Childrens Cancer Research Unit, Kids Research Institute, The Childrens Hospital at Westmead, Westmead, New South Wales, Australia.
  2. Discipline of Childhood and Adolescent Health, The University of Sydney, Sydney, New South Wales, Australia.

Glioma brain tumours are characteristically highly infiltrative into the surrounding healthy brain tissue, which is a mechanically soft tissue environment. Thus mechanisms of cancer cell invasion that have been defined using hard plastic dishes may not apply for the dissemination of glioma brain cancer cells through brain tissue. Indeed, high grade gliomas characteristically lose expression of the high molecular weight tropomyosins, a class of actin-associating proteins that are essential regulators of the actin stress fibres and focal adhesions that underpin cell migration on hard 2-dimensional surfaces. Thus in the present study we have investigated how loss of the high molecular weight tropomyosins affects glioma cell morphology using soft matrices that better recapitulate the biomechanical attributes of the brain. We show that Tpm 2.1 is down-regulated in glioma cells grown on soft brain-like environments. Next we demonstrate that Tpm 2.1 depletion by siRNA induces cell spreading and elongation in soft 3D hydrogels, irrespective of matrix composition, and further that this mimics the effects of Rho kinase inhibition. Tpm 1.7, a second high molecular weight tropomyosin is also down-regulated when 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 high grade glioma cells correlates with elongated, mesenchymal invasion in 3D. We propose that Tpm 2.1 down-regulation overcomes the rigidity-sensing mechanism that would otherwise prevent the cells from spreading throughout the soft brain environment. The unique organisation of the glioma actin cytoskeleton organisation that is highly suited to the soft brain like environment may provide novel therapeutic targets for arresting invasion of high grade glioma cells.