Uncovering the Underlying Biophysical Mechanisms of Directed Cell Migration

Matrix-guided cell migration is fundamental to tissue formation, and its dysregulation is crucial in various diseases. Despite this importance, how cells coordinate probing their environment with forward movement remains unknown. This project examines actin cytoskeletal networks and adhesion receptors as integral yet distinct subsystems — akin to an airplane’s wings and tail, which are critical for lift, stability, and steering. Just as both the ailerons and rudder are necessary for an airplane’s maneuvering yet are ineffective in isolation, this project will explore the interdependence of actin network subsystems in steering and powering cell migration. Using nanofabricated matrices designed to direct cellular behavior towards single migration behaviors, the study will identify the parts within each subsystem and how they interact to create matrix-guided migration. The broader impacts include engaging high school students in cell motility challenge experiments using student-designed nanofabricated matrices and establishing ‘The A-mazing Cell Races’ website to present the results and engage the public with the dynamics of cell biology. The project’s innovative strategy of forcing a single cellular function and identifying the parts that create the function is a transformative approach to studying complex systems that cannot be separated using traditional biochemical or molecular approaches. Cells use actin-based protrusions to probe the ECM for places to bind and form anchors to pull themselves forward. Extensive studies have revealed that protrusions contain multiple actin networks with different structures. However, understanding each network’s role in probing and forward movement has been limited. The networks cannot be isolated without inducing compensatory effects, and they cannot probe or bind ECM without receptors. Yet, the networks are not thought to connect to receptors until the receptors bind to ECM. This proposal targets these significant gaps by considering actin networks and ECM receptors as complex systems, an assembly of parts that produces more functionality than its components. However, as many of us learned as children who took something apart to figure out how it worked and ended up with a box of parts that could not be put back together, some hidden randomness, hierarchy, or collective dynamic essential for functionality disappears when pieces are removed. This project will study ECM-guided cell migration as a complex system composed of non-separable, hierarchical, interactive, dynamic ECM receptor–actin network subsystems that regulate probing and forward migration. Using nanofabricated ECM substrates will identify the subsystems and determine how they respond to substrate cues at the cellular, sub-cellular, and single-molecule levels. Challenging the cells to engage multiple subsystems to navigate complex challenges using ECM mazes will define the subsystem hierarchy of action for each choice and enable the use of graph theory to model cells navigating these complex challenges. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.