TMIC-13. FEELING THE FORCE: DIFFERENCES IN THE MECHANOREGULATED MIGRATION OF HIGH GRADE GLIOMA BETWEEN INDIVIDUAL CELLS AND THOSE IN CONTACT WITH OTHER TUMOUR CELLS

摘要

A major limitation in the treatment of High Grade Gliomas (HGG) is their highly disseminating nature. While it is increasingly appreciated that the mechanical properties of the extracellular matrix, (measured as tissue elasticity, Young’s modulus, E), can independently cue cancer cell migration and invasion, to date there has been little consideration of this mechanism in HGG invasion. This is particularly important given that the brain parenchyma is a mechanically soft tissue (E values varying between 1 - 10 kPa). By measuring single cell migration we have previously demonstrated that molecular subclasses of HGGs exhibit different rigidity-sensitive and -insensitive migration. Following these findings, the present project aimed to determine whether these mechanosensitive phenotypes are maintained in the dissemination of multicellular tumour spheroids (MCTSs) that represent in vivo organisation of the primary tumour bulk. Therefore MCTSs composed of primary patient-derived HGG cells with pre-established single cell mechanosensitive phenotypes were cultured on mechanically tuneable polyacrylamide hydrogels, mimicking the range of physiological tissue rigidities. Bright-field time-lapse images were then captured over a period of 48 hours, 6 images per hour. In order to quantitate the migratory behaviours, we adapted a previously published automated image analysis program to segment the MCTS images into proliferative and migratory regions. Our analysis suggests that the cellular mechano-phenotype is affected by contact with neighbouring cells, as the migratory response to tissue stiffness is quantitatively different in the MCTSs. Our results highlight different migratory behaviour between HGG cells within the primary tumour mass versus individual cells that escape. Our results reveal the complex migratory behaviour of HGG cells and suggests that successful anti-invasive therapies will need different strategies depending on tumour cell location.