Molecular noise restricts the ability of an individual cell to resolve input signals of different strengths and gather information about the external environment. Transmitting information through complex signaling networks with redundancies can overcome this limitation. We developed an integrative theoretical and experimental framework, based on the formalism of information theory, to quantitatively predict and measure the amount of information transduced by molecular and cellular networks. Analyzing tumor necrosis factor (TNF) signaling revealed that individual TNF signaling pathways transduce information sufficient for accurate binary decisions, and an upstream bottleneck limits the information gained via multiple pathways together. Negative feedback to this bottleneck could both alleviate and enhance its limiting effect, despite decreasing noise. Bottlenecks likewise constrain information attained by networks signaling through multiple genes or cells.

Living cells and the extracellular matrix (ECM) can display complex interactions that define key developmental, physiological and pathological processes. Here, we report a new type of directed migration — which we term ‘topotaxis’ — by which cell movement is guided by the gradient of the nanoscale topographic features in the cells’ ECM environment. We show that the direction of topotaxis is reflective of the effective cell stiffness, and that it depends on the balance of the ECM-triggered signalling pathways PI3K-Akt and ROCK-MLCK. In melanoma cancer cells, this balance can be altered by different ECM inputs, pharmacological perturbations or genetic alterations, particularly a loss of PTEN in aggressive melanoma cells. We conclude that topotaxis is a product of the material properties of cells and the surrounding ECM, and propose that the invasive capacity of many cancers may depend broadly on topotactic responses, providing a potentially attractive mechanism for controlling invasive and metastatic behaviour.

Cell polarization and directional cell migration can display random, persistent, and oscillatory dynamic patterns. However, it is not clear whether these polarity patterns can be explained by the same underlying regulatory mechanism. Here, we show that random, persistent, and oscillatory migration accompanied by polarization can simultaneously occur in populations of melanoma cells derived from tumors with different degrees of aggressiveness. We demonstrate that all of these patterns and the probabilities of their occurrence are quantitatively accounted for by a simple mechanism involving a spatially distributed, mechanochemical feedback coupling the dynamically changing extracellular matrix (ECM)-cell contacts to the activation of signaling downstream of the Rho-family small GTPases. This mechanism is supported by a predictive mathematical model and extensive experimental validation, and can explain previously reported results for diverse cell types. In melanoma, this mechanism also accounts for the effects of genetic and environmental perturbations, including mutations linked to invasive cell spread. The resulting mechanistic understanding of cell polarity quantitatively captures the relationship between population variability and phenotypic plasticity, with the potential to account for a wide variety of cell migration states in diverse pathological and physiological conditions. cell polarization | cell migration | mechanochemical feedback | Rho-family small GTPases | extracellular matrix C ell migration involves complex interactions with the extracellular matrix (ECM) (1-4). Beyond providing cells with the substratum for adhesion and traction during the migration process, the ECM can activate signaling networks through biochemical engagement of the integrin complexes within focal adhesions (FAs) (5-7). The signaling pathways activated by integrins can impinge on the Rho-family small GTPases that are thought to be central regulators of cell polarity and migration (8-10). Varying ECM density can differentially control activation of two proteins belonging to this family, Rac1 and RhoA, which frequently display antagonistic interactions (11,12). Activation of Rac1 and RhoA can in turn regulate the mechanical properties of the cell, thus influencing how the cell interfaces with complex local organization of ECM fibers (13-15). The intricate nature of this ECM-Rac1-RhoA feedback interaction and the wide diversity of topographic ECM structures have made comprehensive analysis of the resulting cell migration behavior very challenging.In vivo cell migration can display diverse dynamic patterns. It can vary from random exploratory migration characterized by poor FA formation, frequent pseudopod extension, and a lack of stress fibers in dense 3D ECM (so-called 3D cell migration) to highly persistent migration along single ECM fibers in sparse 3D ECM (essentially 1D cell migration) (16-18). Recently, oscillatory migration patterns have also been observed following perturbation of cytoskeletal components, with cells retra...