Membrane Flow Drives an Adhesion-Independent Amoeboid Cell Migration Mode

Cells migrate by applying rearward forces against extracellular media. It is unclear how this is achieved in amoeboid migration, which lacks adhesions typical of lamellipodia-driven mesenchymal migration. To address this question, we developed optogenetically controlled models of lamellipodia-driven and amoeboid migration. On a two-dimensional surface, migration speeds in both modes were similar. However, when suspended in liquid, only amoeboid cells exhibited rapid migration accompanied by rearward membrane flow. These cells exhibited increased endocytosis at the back and membrane trafficking from back to front. Genetic or pharmacological perturbation of this polarized trafficking inhibited migration. The ratio of cell migration and membrane flow speeds matched the predicted value from a model where viscous forces tangential to the cell-liquid interface propel the cell forward. Since this mechanism does not require specific molecular interactions with the surrounding medium, it can facilitate amoeboid migration observed in diverse microenvironments during immune function and cancer metastasis. •Optogenetic RhoA or GPCR activation drives amoeboid or lamellipodial cell migration•Only the amoeboid mode exhibits rearward plasma membrane flow•Both modes propel adherent cells, but only the amoeboid mode propels suspended cells•Tangential viscous forces at the cell surface drive adhesion-independent migration O'Neill et al. use optogenetic control of two distinct migration modes to address the question of how propelling forces are generated during adhesion-independent cell migration. They show that rearward plasma membrane flow generates tangential viscous forces at the cell-liquid interface to drive the cell forward.