Cells can migrate through tight spaces by adopting an amoeboid-like motility, characterized by blebbing and minimal proteolytic degradation of the surrounding extracellular matrix (ECM). Driscoll et al. report that amoeboid-like migration can create ECM tunnels by a process they term ‘worrying’, in which large blebs abrade collagen.

The authors used melanoma cells, known for amoeboid migration, and found that they form rounded cells with small transient blebs when transplanted into zebrafish. Melanoma cells in 3D collagen in vitro adopted either faster-moving extended mesenchymal, or slower-moving rounded, morphologies, with the latter associated with more metastatic melanomas. The amoeboid cells formed tunnels through collagen even with protease inhibitors, which suggests that tunnelling is independent of proteolysis. Instead, repeated bleb protrusion and retraction slowly fragment collagen and internalize collagen fragments. The authors found that polarized bleb formation is downstream of PI3K and ARP2/3-mediated actin polymerization.