(722e) Cell Sensing and Decision-Making in Confinement: The Role of TRPM7 in a Tug of War between Hydraulic Pressure and Cross-Sectional Area

Cells sense, integrate and interpret the diverse chemical and physical cues of the local microenvironment, such as chemotactic and/or adhesion site gradients, ECM stiffness and composition, confinement and hydraulic pressure, to define a direction of migration and the underlying motility mechanisms. Plasticity broadens the repertoire of migration modes and mechanisms employed by tumor cells (i.e., mesenchymal versus bleb-based migration), and enables them to optimize their directed locomotion in different microenvironments. Directional dilemmas imposed by intersections of confining channel-like tracks in vivo present an additional layer of complexity in the directional decision and migratory mechanisms of cells. How cells sense hydraulic pressure and make directional choices in confinement remains elusive. Using trifurcating Ψ-like microchannels of different hydraulic resistances and cross-sectional areas, we discovered that the TRPM7 ion channel is the critical mechanosensor, which directs decision-making of blebbing cells towards channels of lower hydraulic resistance irrespective of their cross-sectional areas. Hydraulic pressure-mediated TRPM7 activation triggers calcium influx and supports a thicker cortical actin meshwork containing an elevated density of myosin-IIA motors. Inhibition of TRPM7 function or actomyosin contractility renders cells unable to sense or act upon different resistances and alters the decision-making pattern to cross-sectional area-based partition. Cortical actomyosin shields cells against external forces and facilitates cell entrance in low resistance channels. Cell distribution in microchannels is predicted by the maximum entropy principle using cortical actin as key variable. This study demonstrates the unique role of TRPM7 in controlling decision-making and navigating migration in complex microenvironments.