Cell–3D matrix interactions: recent advances and opportunities

Significant research over the past two decades has established that extracellular matrix (ECM) elasticity, or stiffness, impacts fundamental cell processes including spreading, growth, proliferation, migration, differentiation, and organoid formation. Linearly elastic polyacrylamide hydrogels and polydimethylsiloxane (PDMS) elastomers coated with ECM proteins have become widely-used tools for assessing the role of stiffness, and results from these experiments are often assumed to reproduce the effect of the mechanical environment experienced by cells in vivo . However, tissues and ECMs are not linearly elastic materials – they in fact exhibit far more complex mechanical behaviors, including viscoelasticity, or a time-dependent response to loading or deformation, as well as mechanical plasticity and nonlinear elasticity. Recent work has revealed that matrix viscoelasticity regulates these same fundamental cell processes, and importantly can promote behaviors not observed with elastic hydrogels in both 2D and 3D culture microenvironments. These important findings have provided new insights into cell-matrix interactions and have given context as to how these interactions differentially modulate mechano-sensitive molecular pathways in cells. Moreover, these results indicate new design guidelines for the next generation of biomaterials that better match tissue and ECM mechanics for in vitro tissue models and applications in regenerative medicine.

Cell migration is essential for physiological processes as diverse as development, immune defence and wound healing. It is also a hallmark of cancer malignancy. Thousands of publications have elucidated detailed molecular and biophysical mechanisms of cultured cells migrating on flat, 2D substrates of glass and plastic. However, much less is known about how cells successfully navigate the complex 3D environments of living tissues. In these more complex, native environments, cells use multiple modes of migration, including mesenchymal, amoeboid, lobopodial and collective, and these are governed by the local extracellular microenvironment, specific modalities of Rho GTPase signalling and non-muscle myosin contractility. Migration through 3D environments is challenging because it requires the cell to squeeze through complex or dense extracellular structures. Doing so requires specific cellular adaptations to mechanical features of the extracellular matrix (ECM) or its remodelling. In addition, besides navigating through diverse ECM environments and overcoming extracellular barriers, cells often interact with neighbouring cells and tissues through physical and signalling interactions. Accordingly, cells need to call on an impressively wide diversity of mechanisms to meet these challenges. This Review examines how cells use both classical and novel mechanisms of locomotion as they traverse challenging 3D matrices and cellular environments. It focuses on principles rather than details of migratory mechanisms and draws comparisons between 1D, 2D and 3D migration.

The extracellular matrix is a fundamental, core component of all tissues and organs, and is essential for the existence of multicellular organisms. From the earliest stages of organism development until death, it regulates and fine-tunes every cellular process in the body. In cancer, the extracellular matrix is altered at the biochemical, biomechanical, architectural and topographical levels, and recent years have seen an exponential increase in the study and recognition of the importance of the matrix in solid tumours. Coupled with the advancement of new technologies to study various elements of the matrix and cell-matrix interactions, we are also beginning to see the deployment of matrix-centric, stromal targeting cancer therapies. This Review touches on many of the facets of matrix biology in solid cancers, including breast, pancreatic and lung cancer, with the aim of highlighting some of the emerging interactions of the matrix and influences that the matrix has on tumour onset, progression and metastatic dissemination, before summarizing the ongoing work in the field aimed at developing therapies to co-target the matrix in cancer and cancer metastasis.