Collective invasion of glioma cells through OCT1 signalling and interaction with reactive astrocytes after surgery

Abstract

Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer with a short median survival time. GBM is characterized by the hallmarks of aggressive proliferation and cellular infiltration of normal brain tissue. miR-451 and its downstream molecules are known to play a pivotal role in regulation of the balance of proliferation and aggressive invasion in response to metabolic stress in the tumour microenvironment (TME). Surgery-induced transition in reactive astrocyte populations can play a significant role in tumour dynamics. In this work, we develop a multi-scale mathematical model of miR-451-LKB1-AMPK-OCT1-mTOR pathway signalling and individual cell dynamics of the tumour and reactive astrocytes after surgery. We show how the effects of fluctuating glucose on tumour cells need to be reprogrammed by taking into account the recent history of glucose variations and an AMPK/miR-451 reciprocal feedback loop. The model shows how variations in glucose availability significantly affect the activity of signalling molecules and, in turn, lead to critical cell migration. The model also predicts that microsurgery of a primary tumour induces phenotypical changes in reactive astrocytes and stem cell-like astrocytes promoting tumour cell proliferation and migration by Cxcl5. Finally, we investigated a new anti-tumour strategy by Cxcl5-targeting drugs. This article is part of the theme issue ‘Multi-scale analysis and modelling of collective migration in biological systems’.