Integrating in vitro experiments with in silico approaches for Glioblastoma invasion: the role of cell-to-cell adhesion heterogeneity

Abstract

Glioblastoma cells adopt migration strategies to invade into the brain parenchyma ranging from individual to collective mechanisms, whose role and dynamics are not yet fully understood. In this work, we explore Glioblastoma heterogeneity and recapitulate its invasive patterns both in vitro, by utilizing primary cells along with the U87MG cell line, and in silico, by adopting discrete, individual cell-based mathematics. Glioblastoma cells are cultured three-dimensionally in an ECM-like substrate. The primary Glioblastoma spheroids adopt a novel cohesive pattern, mimicking perivascular invasion in the brain, while the U87MG adopt a typical, starburst invasive pattern under the same experimental setup. Mathematically, we focus on the role of the intrinsic heterogeneity with respect to cell-to-cell adhesion. Our proposed mathematical approach mimics the invasive morphologies observed in vitro and predicts the dynamics of tumour expansion. The role of the proliferation and migration is also explored showing that their effect on tumour morphology is different per cell type. The proposed model suggests that allowing cell-to-cell adhesive heterogeneity within the tumour population is sufficient for variable invasive morphologies to emerge which remain originally undetectable by conventional imaging, indicating that exploration in pathological samples is needed to improve our understanding and reveal potential patient-specific therapeutic targets.