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.

Gliomas are malignant tumors that are commonly observed in primary brain cancer. Glioma cells migrate through a dense network of normal cells in microenvironment and spread long distances within brain. In this paper we present a two-dimensional multiscale model in which a glioma cell is surrounded by normal cells and its migration is controlled by cell-mechanical components in the microenvironment via the regulation of myosin II in response to chemoattractants. Our simulation results show that the myosin II plays a key role in the deformation of the cell nucleus as the glioma cell passes through the narrow intercellular space smaller than its nuclear diameter. We also demonstrate that the coordination of biochemical and mechanical components within the cell enables a glioma cell to take the mode of amoeboid migration. This study sheds lights on the understanding of glioma infiltration through the narrow intercellular spaces and may provide a potential approach for the development of anti-invasion strategies via the injection of chemoattractants for localization.

The dynamics of an elastic rod in a viscous fluid at zero Reynolds number is investigated when the bottom end of the rod is tethered at a point in space and rotates at a prescribed angular frequency, while the other part of the rod freely moves through the fluid. A rotating elastic rod, which is intrinsically straight, exhibits three dynamical motions: twirling, overwhirling, and whirling. The first two motions are stable, whereas the last motion is unstable. The stability of dynamical motions is determined by material and geometrical properties of the rod, fluid properties, and the angular frequency of the rod. We employ the regularized Stokes flow to describe the fluid motion and the Kirchhoff rod model to describe the elastic rod. Our simulation results display subcritical Hopf bifurcation diagrams indicating the bistability region. We also investigate the whirling motion generated by the rotation of an intrinsically bent rod. It is observed that the angular frequency determines the handedness of the whirling rod and thus the flow direction and that there is a critical frequency which separates the positive (upward) flow at frequencies above it from the negative (downward) flow at frequencies below it.

The helical flagella that are attached to the cell body of bacteria such as Escherichia coli and Salmonella typhimurium allow the cell to swim in a fluid environment. These flagella are capable of polymorphic transformation in that they take on various helical shapes that differ in helical pitch, radius, and chirality. We present a mathematical model of a single flagellum described by Kirchhoff rod theory that is immersed in a fluid governed by Stokes equations. We perform numerical simulations to demonstrate two mechanisms by which polymorphic transformation can occur, as observed in experiments. First, we consider a flagellar filament attached to a rotary motor in which transformations are triggered by a reversal of the direction of motor rotation [L. Turner et al., J. Bacteriol. 182, 2793 (2000)]. We then consider a filament that is fixed on one end and immersed in an external fluid flow [H. Hotani, J. Mol. Biol. 156, 791 (1982)]. The detailed dynamics of the helical flagellum interacting with a viscous fluid is discussed and comparisons with experimental and theoretical results are provided.

Multi-flagellated bacteria such as E. coli exploit the polymorphic transformations of helical flagella to explore their fluid environment. In these bacteria, a sequence of polymorphic helical forms appears consecutively as the cell 'runs' and 'tumbles.' During a run, the molecular motors that drive the twirling flagella spin counterclockwise , and the flagella form a normal flagellar bundle. Reversing one or more of these motors, from counterclockwise to clockwise, initiates a tumble by inducing shape transformations of the associated filaments, from normal to semicoiled and then to curly 1 forms. The next run begins when the motors switch back to counterclockwise rotations. This causes the flagella to revert from curly 1 back to normal forms. This paper investigates the dynamics of elastic flagella when one or two flagella undergo a full cycle of polymorphic transformations using a computational method in which the flagellar motors are tethered in space and connected via flexible hooks to the filaments. We describe the flagellar filaments and their hooks as elastic rods adopting Kirchhoff rod theory, and their hydrodynamic interaction using a generalization of the method of regularized Stokeslets. We also investigate the role of a compliant hook in flagellar bundling.