Emerging data indicate that hypoxia and the extracellular matrix (ECM) together might have a crucial role in metastasis. In this Opinion article the authors suggest a model in which multiple microenvironmental signals might converge to synergistically influence metastatic outcome. Of the deaths attributed to cancer, 90% are due to metastasis, and treatments that prevent or cure metastasis remain elusive. Emerging data indicate that hypoxia and the extracellular matrix (ECM) might have crucial roles in metastasis. During tumour evolution, changes in the composition and the overall content of the ECM reflect both its biophysical and biological properties and these strongly influence tumour and stromal cell properties, such as proliferation and motility. Originally thought of as independent contributors to metastatic spread, recent studies have established a direct link between hypoxia and the composition and the organization of the ECM, which suggests a new model in which multiple microenvironmental signals might converge to synergistically influence metastatic outcome.

A multitude of cellular and subcellular processes depend critically on the mechanical deformability of the cytoplasm. We have recently introduced the method of particle-tracking microrheology, which measures the viscoelastic properties of the cytoplasm locally and with high spatiotemporal resolution. Here we establish the basic principles of particle-tracking microrheology, describing the advantages of this approach over more conventional approaches to cell mechanics. We present basic concepts of molecular mechanics and polymer physics relevant to the microrheological response of cells. Particle-tracking microrheology can probe the mechanical properties of live cells in experimentally difficult, yet more physiological, environments, including cells embedded inside a 3D matrix, adherent cells subjected to shear flows, and cells inside a developing embryo. Particle-tracking microrheology can readily reveal the lost ability of diseased cells to resist shear forces.

Defects in nuclear morphology often correlate with the onset of disease, including cancer, progeria, cardiomyopathy, and muscular dystrophy. However, the mechanism by which a cell controls its nuclear shape is unknown. Here, we use adhesive micropatterned surfaces to control the overall shape of fibroblasts and find that the shape of the nucleus is tightly regulated by the underlying cell adhesion geometry. We found that this regulation occurs through a dome-like actin cap that covers the top of the nucleus. This cap is composed of contractile actin filament bundles containing phosphorylated myosin, which form a highly organized, dynamic, and oriented structure in a wide variety of cells. The perinuclear actin cap is specifically disorganized or eliminated by inhibition of actomyosin contractility and rupture of the LINC complexes, which connect the nucleus to the actin cap. The organization of this actin cap and its nuclear shape-determining function are disrupted in cells from mouse models of accelerated aging (progeria) and muscular dystrophy with distorted nuclei caused by alterations of A-type lamins. These results highlight the interplay between cell shape, nuclear shape, and cell adhesion mediated by the perinuclear actin cap.