Metastasis is a complex, multistep process responsible for >90% of cancer-related deaths. In addition to genetic and external environmental factors, the physical interactions of cancer cells with their microenvironment, as well as their modulation by mechanical forces, are key determinants of the metastatic process. We reconstruct the metastatic process and describe the importance of key physical and mechanical processes at each step of the cascade. The emerging insight into these physical interactions may help to solve some long-standing questions in disease progression and may lead to new approaches to developing cancer diagnostics and therapies.

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.LINC complexes ͉ nucleus I n 1921, Champy and Carleton suggested an apparent correlation between the shape of various types of animal cells and the shape of their respective nuclei (1). Moreover, defects in nuclear shape are routinely used in the lab and in clinical settings as markers of disease and differentiation in human cells and tissues (2). However, remarkably little is known about the factors that determine nuclear morphology in living cells. In particular, the molecular mechanisms that govern the shape of the interphase nucleus are unknown. Here we show that an actin filament structure that forms a cap or dome located above the apical surface of the nucleus tightly controls nuclear shape and identify key associated cytoskeletal regulators of its organization and nuclear shape-determining function. The organization and function of the perinuclear actin cap are deregulated in diseased cells with distorted nuclei. Results and DiscussionTo test the hypothesis of a correlation between the shape of the nucleus and the overall cell shape, mouse embryonic fibroblasts were dispersed on fibronectin (FN)-coated glass substrates. Using morphometric analysis, we found that nuclear shape and cellular shape correlated ( Fig. 1 A and B). Shape factor, defined as 4 A/P 2 (where A and P are the nuclear area and perimeter), approaches 1 for a rounded nucleus and approaches 0 for an elongated nucleus. Elongated cells typically showed an elongated nucleus of low shape factor; rounded cells showed a rounded nucleus of high shape factor (Fig. 1 A). To control cell shape and, therefore, be able to quantify nuclear shape as a function of cell shape, we developed adhesive FN-coated micropatterned stripes of width ranging between 10 and 50 m, which alternated with stripes covered with nonadhesive poly...

The goal of gene therapy is to introduce foreign genes into somatic cells to supplement defective genes or provide additional biological functions, and can be achieved using either viral or synthetic non-viral delivery systems. Compared with viral vectors, synthetic gene-delivery systems, such as liposomes and polymers, offer several advantages including ease of production and reduced risk of cytotoxicity and immunogenicity, but their use has been limited by the relatively low transfection efficiency. This problem mainly stems from the difficulty in controlling their properties at the nanoscale. Synthetic inorganic gene carriers have received limited attention in the gene-therapy community, the only notable example being gold nanoparticles with surface-immobilized DNA applied to intradermal genetic immunization by particle bombardment. Here we present a non-viral gene-delivery system based on multisegment bimetallic nanorods that can simultaneously bind compacted DNA plasmids and targeting ligands in a spatially defined manner. This approach allows precise control of composition, size and multifunctionality of the gene-delivery system. Transfection experiments performed in vitro and in vivo provide promising results that suggest potential in genetic vaccination applications.

It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain. Since Ehrlich's first experiments, only a small number of molecules, such as alcohol and caffeine have been found to cross the blood-brain barrier, and this selective permeability remains the major roadblock to treatment of many central nervous system diseases. At the same time, many central nervous system diseases are associated with disruption of the blood-brain barrier that can lead to changes in permeability, modulation of immune cell transport, and trafficking of pathogens into the brain. Therefore, advances in our understanding of the structure and function of the blood-brain barrier are key to developing effective treatments for a wide range of central nervous system diseases. Over the past 10 years it has become recognized that the blood-brain barrier is a complex, dynamic system that involves biomechanical and biochemical signaling between the vascular system and the brain. Here we reconstruct the structure, function, and transport properties of the blood-brain barrier from an engineering perspective. New insight into the physics of the blood-brain barrier could ultimately lead to clinical advances in the treatment of central nervous system diseases.