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’.

Role of neutrophil extracellular traps in regulation of lung cancer invasion and metastasis: Structural insights from a computational model

“…The whole process includes an initial strong adhesion process between a CTC and TANs involving selectins/integrins/ICAM1, and a series of signaling networks for CTC-EC adhesion, increased permeability from physical contraction of ECs, and the final extravasation [ 104 , 113 , 114 ]. A multi-scale model [ 115 ] may explain the fundamental mechanism behind this complex process in more detail by taking into account specific cell-cell adhesion [ 116 ], ECM-cell interaction [ 117 ], mechanical stress [ 81 , 93 , 95 ], fluid flow [ 118 ], and intracellular signaling of cellular process [ 38 , 93 ].…”

“…Mathematical models of tumor microenvironment and tumor-immune system interactions have been developed: fibroblasts-tumor [ 33 – 35 ], macrophages-tumor [ 36 , 37 ], astrocytes-tumor [ 38 ], NK cells-tumor [ 39 – 41 ], neutrophil-tumor [ 42 , 43 ], tumor-endothelial [ 44 ], and immune-tumor [ 45 , 46 ] interactions. However, the detailed mechanism of tumor invasion and metastasis via communication with TANs is still poorly understood.…”

Multi-scale analysis and modelling of collective migration in biological systems

“…The contribution by Kim et al [85] focuses on glioblastoma multiforme (GBM) which is the most aggressive and malignant brain tumour. GBM is characterized by aggressive proliferation and cellular infiltration of healthy brain tissue.…”

“…It has been speculated that surgery-mediated effects could play a major role. Kim et al [85] define a mathematical model to study the implications of surgery on the dynamics of reactive astrocytes in the tumour microenvironment and test the following hypothesis: astrocyte injury from surgery induces a transition of reactive astrocytes into a stem cell-like phenotype which secretes the chemokine Cxcl5. This signal in turn promotes GBM proliferation and migration through the miR-451-LKB1-AMPK-OCT1-mTor signalling pathway, which is known to regulate GBM proliferation and invasion.…”

Mathematical model of STAT signalling pathways in cancer development and optimal control approaches

“…Mathematical modelling is a useful tool in revealing the fundamental mechanism in various cancers [5,[28][29][30][31], interactions with other cells [9,[32][33][34] including immune cells [7,35,36], cellular invasion [37], chemotherapy of cancer [35,38,39], apoptosis mechanism [6,35,40,41], and specific signalling pathways [8] such as JAK-STAT [42,43], MYC-p53 [4] and microRNAs [3]. For example, mathematical models of Bcl-2 signalling networks illustrated the importance of molecular play including intrinsic Bcl-2 apoptosis pathway [44][45][46][47][48], bistability in apoptosis [49], interaction between p53 and Bcl-2 [50], VEGF- Bcl-2 in angiogenesis [51,52] and MOMP regulation in pattern recognition [53].…”