Fig. 3. The hybrid E/M state provides plasticity and the local TME dictates collective and individual migration strategies.

In a low stiffness environment, hybrid E/M cells migrate individually through ECM networks in an amoeboid or mesenchymal fashion. Amoeboid cells move through existing openings in a soft ECM of high porosity using few ECM adhesions and stress fibres, independent of protease activity. Mesenchymal migration in regions of somewhat higher stiffness and lower porosity is accompanied by increased formation of ECM adhesions, stress fibres and actomyosin contractility, and requires protease activity (mediated for instance by matrix metalloproteases (MMPs)) to generate openings through which to migrate. A further increase in TME stiffness promotes collective migration of hybrid E/M cells. Collective migration can take the shape of cell clusters or multicellular strands and involves contractile and proteolytically active leader cells creating the path for follower cells. Collectively migrating cells can make use of pre-existing large-scale mechanical structures in the TME such as channels or interphases between cell layers. Interconversion between the different migration strategies is dictated by local variations in the mechanical aspects of the TME, and the hybrid E/M state provides tumour cells with enhanced plasticity to respond to such cues.