Cancer biologists have long understood that tumor transformation and metastasis are driven by both intrinsic genomic changes in the constituent tumor cells and the integrated response of the tissue or organ to extrinsic soluble cues, such as growth factors, cytokines, and chemotactic stimuli. Indeed, cancer progression is often collectively conceptualized and portrayed as a “journey” in which a cell morphs over time from a benign phenotype into an invasive or metastatic entity, with many potential intermediate steps along the way. In practice, the stages of this journey are marked by a variety of genetic and histopathological checkpoints, including amplification or inactivation of specific genes, expression of tumor markers, and stereotypic alterations in cell and tissue architecture. Over the past two decades, however, the field has begun to appreciate that an important part of this journey involves changes in the mechanical
phenotype of the cell and tissue, as reflected both in intrinsic changes in cell and tissue structure and mechanics and in the biophysical properties of the cell’s microenvironment, such as the mechanics, geometry, and topology of the extracellular matrix (ECM) [1
]. The interplay between the biophysical properties of the cell and ECM establishes a dynamic, mechanical reciprocity between the cell and the ECM in which the cell’s ability to exert contractile stresses against the extracellular environment balances the elastic resistance of the ECM to that deformation (i.e., ECM rigidity or elasticity). It has now become clear that this force balance can regulate a surprisingly wide range of cellular properties that are all critical to tumorigenesis, including structure, motility, proliferation, and differentiation.
Cells sense, process, and respond to mechanical and other biophysical cues from the ECM using an interconnected hierarchy of mechanochemical systems that includes adhesion receptors (e.g., integrins), intracellular focal adhesions, cytoskeletal networks, and molecular motors. The integrated mechanics and dynamics of these systems enable cells to control their shape, generate force, and ultimately remodel the ECM [4
]. These structural networks also interact in very specific ways with canonical signal transduction pathways to orchestrate cell behavior. For example, mammary epithelial cells (MECs) form normal acinar structures when cultured in ECMs of physiological stiffness but display the structural and transcriptional hallmarks of a developing tumor when cultured in ECMs of a stiffness that more closely resembles tumor stroma. Processing of these signals requires integrin clustering, ERK activation, cytoskeletal remodeling and Rho GTPase-dependent contractility, illustrating functional connections between growth factor signaling, mechanotransductive signaling, and the cell’s cytoskeletal, adhesive, and contractile machinery [9
]. In other words, micromechanical signals from the ECM and cell structural control are intimately connected and interface with signal transduction networks to control fundamental behaviors relevant to tumor transformation, invasion, and metastasis.
In this review, we discuss the evolution of the mechanical phenotype of tumor cells, which we conceptualize as a “force journey.” We begin by discussing the various stages of this journey, including mechanical forces that cells within tissues must encounter and generate while transforming from a normal to an invasive or metastatic phenotype. We then review methods for measuring cellular mechanical properties in vitro and in vivo, including a description of probes of both cortical and intracellular mechanics. Finally, we briefly describe emerging molecular mechanisms for mechanotransduction in tumor cells, with a special emphasis on Rho GTPase and focal adhesion kinase.