Frictiotaxis underlies adhesion-independent durotaxis

Cells move directionally along gradients of substrate stiffness, a process called durotaxis. The current consensus is that durotaxis relies on cell-substrate focal adhesions to sense stiffness and transmit forces that drive directed motion. Therefore, focal adhesion-independent durotaxis is thought to be impossible. Here, we show that confined cells can perform durotaxis despite lacking strong or specific adhesions. This durotactic migration depends on asymmetric myosin distribution and actomyosin retrograde flow. We show that the mechanism of this adhesion-independent durotaxis is that stiffer substrates offer higher friction. We propose a physical model that predicts that non-adherent cells polarise and migrate towards regions of higher friction – a process that we call frictiotaxis. We demonstrate frictiotaxis in experiments by showing that cells migrate up a friction gradient even when stiffness is uniform. Our results broaden the potential of durotaxis to guide any cell that contacts a substrate and reveal a new mode of directed migration based on friction, with implications for immune and cancer cells, which commonly move with non-specific interactions.