Mechanical signaling through the cytoskeleton regulates cell proliferation by coordinated focal adhesion and Rho GTPase signaling

TLDR

Cell shape, spreading, and the forces they generate and sense have been increasingly recognized as key regulators of proliferation, with the microenvironment’s biochemical, structural, and mechanical cues—especially ECM stiffness—providing the context for these mechanical signals. This commentary reviews recent advances in the mechanisms by which mechanical signaling controls cell proliferation, emphasizing 3D microenvironments, in vivo extracellular matrices, and the emerging role of tumor–stromal interactions in breast cancer. Mechanical signaling relies on transcellular cell–ECM or cell–cell adhesions and Rho GTPase‑mediated contractility, which link extracellular forces to cytoskeletal force generators and transmit tension through the cytoskeleton. Recent data reveal that mechanical signaling contributes to breast cancer progression by influencing tumor–stromal interactions, underscoring its potential as a therapeutic target.

Abstract

The notion that cell shape and spreading can regulate cell proliferation has evolved over several years, but only recently has this been linked to forces from within and upon the cell. This emerging area of mechanical signaling is proving to be wide-spread and important for all cell types. The microenvironment that surrounds cells provides a complex spectrum of different, simultaneously active, biochemical, structural and mechanical stimuli. In this milieu, cells probe the stiffness of their microenvironment by pulling on the extracellular matrix (ECM) and/or adjacent cells. This process is dependent on transcellular cell–ECM or cell–cell adhesions, as well as cell contractility mediated by Rho GTPases, to provide a functional linkage through which forces are transmitted through the cytoskeleton by intracellular force-generating proteins. This Commentary covers recent advances in the underlying mechanisms that control cell proliferation by mechanical signaling, with an emphasis on the role of 3D microenvironments and in vivo extracellular matrices. Moreover, as there is much recent interest in the tumor–stromal interaction, we will pay particular attention to exciting new data describing the role of mechanical signaling in the progression of breast cancer.