Wavy geometry controls nuclear morphology, migration, and YAP signaling independent of myosin II contractility

Cell morphology and mechanics are tightly coupled to extracellular matrix (ECM) geometry, yet how non-linear topographies regulate intracellular organization and phenotype remains unclear. Here, we use microfabricated wavy patterns to recapitulate physiologically relevant curvature, such as those found in arteries, and precisely control cell shape. Cells adopting wavy morphologies exhibit enhanced YAP signaling and increased traction forces, accompanied by a reorganization and redistribution of intracellular forces. Live-cell imaging identifies curvature-induced actin arcs that exhibit retrograde flow, actively deforming the nucleus and reorganizing chromatin within wavy geometries. Unlike canonical mechanotransduction, this structural remodeling operates independently of myosin II-mediated contractility and is reminiscent of lamellipodial dynamics. Nuclear deformation increases with curvature yet when the wavy cells are stretched, nuclear strain and YAP translocation are attenuated, indicating the wavy cell structure acts as a mechanical buffer to external load. Despite increased nuclear restriction, wavy cells maintain migration speed but display reduced persistence, indicating a shift in migratory mode rather than impaired motility. Together, our findings identify cell-scale curvature as a key regulator of intracellular structure, mechanotransduction, and migration behavior, revealing how geometric constraints reshape nuclear organization and force distribution to tune cellular phenotype. STATEMENT OF SIGNIFICANCE: Extracellular matrix structure is a critical regulator of tissue function and homeostasis, yet the mechanisms by which non-linear geometries instruct cell function remain poorly investigated. We demonstrate that physiological wavy cell morphology reorganizes the actin cytoskeleton into distinct arcs that physically deform the nucleus and modulate YAP signaling. Crucially, this geometric regulation is independent of canonical non-muscle myosin II contractility and acts as a mechanical buffer to attenuate external strain and confound migration polarization. These findings uncover a geometry-driven mode of mechanotransduction that establishes how tissue-level curvature functions as a structural regulator of cell mechanics and phenotype.