Caveolae and Membrane Tension in Cell Motility – MOTICAV

Cell morphogenesis and motility are crucial processes at all stages of life, from development to tissue homeostasis, and are associated with several pathological states such as cancer. Motile cells have to quickly adapt their morphogenetic programs to the continuous changing microenvironments, which requires a highly regulated spatiotemporal integration of a variety of the mechanical and biochemical clues. Understanding how migrating cells read and interpret these mechano-chemical stimuli remains an outstanding challenge in cell biology today.

The main engine of cell locomotion is the acto-myosin machinery that, by pushing and/or pulling on the plasma membrane (PM), controls the extension of membrane protrusions, the formation of new adhesion sites at the cell front, and the detachment of the cell rear. These processes not only depend upon, but also affect the tension of the cell membrane. In addition, obstacles and geometrical cues encountered during migration will also locally perturb membrane tension. Membrane tension is therefore a key mediator of mechanical cues and has been implicated in the regulation of cell migration.

Partners P1 & P3 recently established that caveolae, the characteristic small plasma membrane invaginations, buffer the abrupt variations of membrane tension induced by mechanical constraints by flattening in the membrane. P1 preliminary data show that caveolae flattening is also associated with the regulation of selective signaling cascades and to the control of the transcription of a number of genes. Moreover P2 preliminary results suggest that caveolae could directly sense tension across the 3D network organized by collagen fibers. While both membrane tension and caveolae are known to regulate some aspects of cell migration, it is not known if membrane tension modulation by caveolae plays a role in cell motility. In this proposal, we aim at investigating the role of caveolae and membrane tension during cell migration. We specifically want to understand how membrane tension buffering by caveolae regulates cell migration. We will determine how caveolae through the control of mechano-signaling pathways and mechanotransduction can impact cell motility. Finally, we will investigate how chemical/mechanical cues sensing by caveolae orientate the direction of migration. The completion of our proposal should provide crucial new information on the role of membrane mechanics in cell migration, by revealing how mechanosensing and mechanotransduction are integrated with the organization and dynamics of the cytoskeleton.