Plasticity in the Macromolecular-Scale Causal Networks of Cell Migration

Heterogeneous and dynamic single cell migration behaviours arise from a complex multi-scale signalling network comprising both molecular components and macromolecular modules, among which cell-matrix adhesions and F-actin directly mediate migration. To date, the global wiring architecture characterizing this network remains poorly defined. It is also unclear whether such a wiring pattern may be stable and generalizable to different conditions, or plastic and context dependent. Here, synchronous imaging-based quantification of migration system organization, represented by 87 morphological and dynamic macromolecular module features, and migration system behaviour, i.e., migration speed, facilitated Granger causality analysis. We thereby leveraged natural cellular heterogeneity to begin mapping the directionally specific causal wiring between organizational and behavioural features of the cell migration system. This represents an important advance on commonly used correlative analyses that do not resolve causal directionality. We identified organizational features such as adhesion stability and adhesion F-actin content that, as anticipated, causally influenced cell migration speed. Strikingly, we also found that cell speed can exert causal influence over organizational features, including cell shape and adhesion complex location, thus revealing causality in directions contradictory to previous expectations. Importantly, by comparing unperturbed and signalling-modulated cells, we provide proof-of-principle that causal interaction patterns are in fact plastic and context dependent, rather than stable and generalizable.