Mechanoregulation of glioblastoma by extracellular biophysical stimuli

Abstract

Glioblastoma is an aggressive and lethal brain cancer characterised by explosive growth, diffuse and infiltrative tumour cell invasion, and a consistently terminal prognosis, regardless of treatment. The dissemination of individual tumour cells into healthy brain tissue complicates treatment and effectively guarantees tumour relapse. However drivers and regulators of cell invasion also offer intriguing potential targets for improved disease treatment and patient survival. A variety of cellular behaviours are regulated by biophysical factors including tissue stiffness and density. Cells probe their environment with contractility (traction forces), detecting these biophysical cues, and regulating their behaviour accordingly. In this way, mechanoregulation is an important and potent regulator of cell behaviours as varied as tissue invasion, protein expression and drug susceptibility. In the current study the impact of extracellular biophysical stimuli and mechanoregulation to clinically relevant cell behaviours were tested both in established (continuously-cultured), and patient-derived primary glioblastoma cell lines. Cell invasion was characterised, then related to cell-generated traction forces which were quantified using 3D traction force microscopy. HMG-CoA-reductase inhibitors (statins) were investigated as a treatment option targeting glioblastoma mechanoregulation pathways, with synergistic interactions revealed between statins and the chemotherapy compound temozolomide. This study highlights a consistent importance for biophysical regulation in glioblastoma. Glioblastoma presents as a muscularly and behaviourally heterogeneous disease, and this was observed in the primary cell models. However the data also indicate unifying biological trends relating traction forces with cell migration. These results offer interesting avenues for future study, and potential targets for treatment. The study highlights both the importance of mechanoregulation in glioblastoma as well as the need for continued research and investigation into the regulatory roles of the extracellular biophysical cues in malignant cell behaviour.