The cellular dispersion and therapeutic control of
glioblastoma, the most aggressive type of primary
brain cancer, depends critically on the migration patterns after surgery and intracellular responses of the individual
cancer cells in response to external biochemical cues in the microenvironment. Recent studies have shown that miR-451 regulates downstream molecules including AMPK/CAB39/MARK and mTOR to determine the balance between rapid proliferation and invasion in response to metabolic stress in the harsh tumor microenvironment. Surgical removal of the main
tumor is inevitably followed by recurrence of the
tumor due to inaccessibility of dispersed
tumor cells in normal brain tissue. In order to address this complex process of cell proliferation and invasion and its response to conventional treatment, we propose a mathematical model that analyzes the intracellular dynamics of the miR-451-AMPK- mTOR-cell cycle signaling pathway within a cell. The model identifies a key mechanism underlying the molecular switches between proliferative phase and migratory phase in response to metabolic stress in response to fluctuating
glucose levels. We show how up- or down-regulation of components in these pathways affects the key cellular decision to infiltrate or proliferate in a complex microenvironment in the absence and presence of time delays and stochastic noise. Glycosylated
chondroitin sulfate proteoglycans (CSPGs), a major component of the extracellular matrix (ECM) in the brain, contribute to the physical structure of the local brain microenvironment but also induce or inhibit
glioma invasion by regulating the dynamics of the CSPG receptor LAR as well as the spatiotemporal activation status of resident astrocytes and
tumor-associated microglia. Using a multi-scale mathematical model, we investigate a CSPG-induced switch between invasive and non-invasive
tumors through the coordination of ECM-cell adhesion and dynamic changes in stromal cells. We show that the CSPG-rich microenvironment is associated with non-invasive
tumor lesions through LAR-
CSGAG binding while the absence of glycosylated CSPGs induce the critical
glioma invasion. We illustrate how high molecular weight CSPGs can regulate the exodus of local reactive astrocytes from the main
tumor lesion, leading to encapsulation of non-invasive
tumor and inhibition of
tumor invasion. These different CSPG conditions also change the spatial profiles of ramified and activated microglia. The complex distribution of CSPGs in the tumor microenvironment can determine the nonlinear invasion behaviors of
glioma cells, which suggests the need for careful therapeutic strategies.