(25h) Mechanotransduction during Confined Cell Migration

Cell locomotion is a fundamental cellular phenomenon that regulates critical (patho)physiological events, including cancer metastasis. In vivo, cells respond to diverse signals and move locally or systemically to reach injured sites. Although prior studies have focused on uncovering the effects of biochemical signals on cell locomotion, little is known about the role of physical cues in this process. Migrating cells frequently experience mechanical challenges, which induce significant deformation of the cell and its nucleus. This deformation is particularly evident as cells transmigrate across the endothelium and/or navigate through confining pores ranging from 1 to 20 µm in diameter and fiber- and channel-like tracks varying from less than 3 up to 30 µm in width. The inability of cells to adapt to the mechanical challenges imposed by their microenvironment often results in complete inhibition of cell motility, as observed at pore sizes smaller than ∼7 µm². Using sophisticated bioengineering, molecular biology and imaging techniques, I will demonstrate that cells sense and respond to 3D confinement by activating RhoA/myosin II, which in turn alter the migration mechanisms and compromise nuclear envelop integrity with detrimental consequences for the genome. I will also discuss the long-term impact of confinement on intracellular signaling, cell proliferation and viability. Our work aims to provide a comprehensive understanding of the role of confinement in cell locomotion, facilitating the development of novel strategies to combat metastasis.