Curved Microfluidic Confinement Reveals Cell-Shape-Dependent Nuclear Mechanotransduction in Adaptive Migration

Cells navigate within diverse curved microenvironments derived from extracellular matrix (ECM) and neighboring cells in vivo. While current studies primarily focus on cell migration on curved surfaces, cellular adaptive responses to confinement-coupled geometric curvature remain largely unexplored. Herein, we design a confined curvature-based microfluidic chip (CCM-Chip) that mimics the physiologically relevant physical cues encountered during cell migration and investigate how cells dynamically answer to local geometric features. In the CCM-Chip, cells exhibit shape bending, nuclear deformation, and cytoskeletal remodeling that correlate with local geometric curvature. We then engineer a microgrooved uniaxial stretching microdevice to manipulate cell shape and find that curvature-induced cell shape results in nuclear envelope stretching, thus initiating downstream nuclear responses. Significantly, the stretched nuclear envelope effectively triggers the recruitment of cPLA2 to the nucleus, with nesprin and SUN1 serving as critical mediators in the process of nuclear mechanotransduction. The cPLA2 activation promotes stress fiber polarization at the cell front and enhances cellular contractility, facilitating curvature-induced cell migration. This work provides a versatile biomimetic microdevice for cell migration studies and highlights the key role of nuclear deformation-induced cPLA2 signaling in adaptive cell migration, advancing the development of therapeutic strategies against cancer metastasis.