Mechanotransduction is the ability of a cell to sense mechanical cues from its microenvironment and convert them into biochemical signals to elicit adaptive transcriptional and other cellular responses. Here, we describe recent advances in the field of mechanical regulation of transcription, highlight mechanical regulation of the epigenome as a key novel aspect of mechanotransduction, and describe recent technological advances that could further elucidate the link between mechanical stimuli and gene expression. In this review, we emphasize the importance of mechanotransduction as one of the governing principles of cancer progression, underscoring the need to conduct further studies of the molecular mechanisms involved in sensing mechanical cues and coordinating transcriptional responses.
Cells and Tissues Respond to the Physical EnvironmentCells in the human body are subject to a wide variety of mechanical stimuli acting at multiple scales. At the single molecule level, receptors on immune cells such as T and B cells leverage force to discriminate between ligands, enabling efficient recognition of antigen [1]. At the singlecell level, mechanical cues guide cell fate decisions in stem cells [2] and migration strategies of cancer cells [3]. Matrix stiffness alters the force generation capability of cancer cells, which scales with metastatic potential [4]. Finally, collective processes such as wound healing, tumorigenesis, and tissue homeostasis are intimately linked with the physical microenvironment [5,6]. In order to engage in functional responses appropriate to both passive mechanical stimuli, such as stiffness or topographic features of the cellular environment, and active ones, such as forces generated by cells and tissues, cells must be able to sense and measure mechanical perturbations. Different elements of the cell act in concert to maintain structural integrity and coordinate cellular sensing of external forces and mechanical stimuli. These stimuli are subsequently transmitted to the nucleus leading to broad changes in chromatin structure and accessibility (Figure 1, Key Figure) [7]. While we have come to appreciate the role of mechanical forces in shaping the genome, the molecular mechanisms involved in mechanotransduction (see Glossary) remain an enigma, with potential long-term implications for physiology, disease, and therapeutics. The focus of this review is to highlight recent advances in understanding the interplay between mechanosensing and transcription, with a particular emphasis on tumorigenesis and cancer progression (Figure 1).
The Cellular Mechanosensing ApparatusThe structural mechanosensing machinery can be broadly classified into two groups: (i) proximal mechanosensing apparatus consisting of cell surface receptors, focal adhesion (FA) complexes, cell-cell junctions, and the actomyosin cytoskeleton, and (ii) proteins of the nuclear envelope. In adherent cells, integrins link the cell to the extracellular matrix (ECM) through FAs (Figure 2). Under applied forces, integrins undergo conforma...
