Mimicking the biomechanical features of the brain for improved identification of effective treatments for brain cancer

Prior VG1,2,5, Vessey JY1, Griffin KR1, Sarker FA1,2, Grundy TJ1,5, Turner K1, Bradbury P1, Mitchell CB1, Day BW3,4 and O'Neill GM1,4,5

  1. Children’s Cancer Research Unit, Kids Research at the Children’s Hospital at Westmead NSW, Australia.
  2. Department of Anatomy & Histology, School of Medical Science, University of Sydney, Sydney, Australia.
  3. Immunology in Cancer & Infection Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
  4. Brain Cancer Discovery Collaborative, Australia.
  5. Discipline of Paediatrics & Child Health, University of Sydney, Sydney, Australia.

Mechanopharmacology is a recently coined term that reflects the role that the physical forces contained within tissues and organs in the body play in proliferation and invasion and, ultimately, cellular response to drugs. Seminal studies in the tissue engineering field revealed that culturing stem cells on matrices which match the softness of brain induced the cells to differentiate into neuronal lineages, independently of any other external factors. While the role for biomechanical forces has begun to be addressed in other solid cancer types, to date there has been limited consideration of this parameter in brain cancer. We hypothesized that mechanosensing (cellular sensing of mechanical forces contained within the surrounding tissue) may alter the biology and response of gliomas to anti-cancer treatments. This was tested using combinations of kinome screening and materials engineered to recapitulate the brain’s soft features, together with primary patient-derived glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG) cells cultured in serum-free media to maintain in vivo characteristics. As a key feature of high grade gliomas is their propensity to migrate and invade widely throughout the brain we used time-lapse imaging and cell tracking to quantify cell migration on a range of soft brain-like matrices. This revealed that the majority of the patient lines exhibited mechanosensitive migration. Kinome screening next identified the putative therapeutic target Aurora Kinase B (AURKB) as a mechanosensitive kinase. Importantly, we have demonstrated that mechanosensitive patient lines are significantly resistant to AURKB inhibitors when cultured on soft surfaces versus plastic. Our studies suggest that the brain’s biomechanical milieu is indeed an important determinant of glioma biology and response to anti-cancer treatments. We propose that assessment of the mechanopharmacology of putative treatments for gliomas should be considered as part of the preclinical assessments in the progression of novel treatments to clinical trial.