Metastasis: crosstalk between tissue mechanics and tumour cell plasticity

Abstract

Despite the fact that different genetic programmes drive metastasis of solid tumours, the ultimate outcome is the same: tumour cells are empowered to pass a series of physical hurdles to escape the primary tumour and disseminate to other organs. Epithelial-to-mesenchymal transition (EMT) has been proposed to drive the detachment of individual cells from primary tumour masses and facilitate the subsequent establishment of metastases in distant organs. However, this concept has been challenged by observations from pathologists and from studies in animal models, in which partial and transient acquisition of mesenchymal traits is seen but tumour cells travel collectively rather than as individuals. In this review, we discuss how crosstalk between a hybrid E/M state and variations in the mechanical aspects of the tumour microenvironment can provide tumour cells with the plasticity required for strategies to navigate surrounding tissues en route to dissemination. Targeting such plasticity provides therapeutic opportunities to combat metastasis.

Fig. 1. EMT regulates cell migration strategies.

Upper row: During epithelial-to-mesenchymal transition (EMT), epithelial cells lose their tight intercellular junctions, form a transient hybrid E/M phenotype, and eventually lose their epithelial features while gaining mesenchymal features. This process is driven by a series of changes in gene transcription programmes. Lower row: migration strategies shift from collective migration, to migration with a high degree of plasticity, to individual migration as EMT progresses.

Fig. 2. Unjamming transitions as an alternative means to trigger migration.

Clusters of cells can switch between solid-like (jammed) and fluid-like (unjammed) states. In this case, changes in mechanical and geometric parameters in the tissue can trigger fluidisation (unjamming) in absence of the changes in gene transcription required for EMT.

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.

Fig. 4. Mechanotransduction drives EMT in response to mechanical cues from the TME.

An increased stiffness in the TME is sensed by integrins, which activate downstream intracellular signalling, ultimately resulting in the nuclear translocation of EMT-associated transcription factors and transcriptional co-activators, such as TWIST and YAP/TAZ. In the nucleus, these factors will bind to and regulate the transcription of target genes such as SNAIL and ZEB, causing a shift between epithelial (E) and mesenchymal (M) features. As tumour cells undergo EMT, cell deformability, proteolytic activity and the formation of invadopodia increase, driving enhanced migratory and invasive capacity.