Matrix rigidity regulates cancer cell growth by modulating cellular metabolism and protein synthesis.

Background: Tumor cells in vivo encounter diverse types of microenvironments both at the site of the primary tumor and at sites of distant metastases. Understanding how the various mechanical properties of these microenvironments affect the biology of tumor cells during disease progression is critical in identifying molecular targets for cancer therapy.

Methodology/principal Findings: This study uses flexible polyacrylamide gels as substrates for cell growth in conjunction with a novel proteomic approach to identify the properties of rigidity-dependent cancer cell lines that contribute to their differential growth on soft and rigid substrates.

Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment.

Current therapies for pancreatic ductal adenocarcinoma (PDA) target individual tumor cells. Focal adhesion kinase (FAK) is activated in PDA, and levels are inversely associated with survival. We investigated the effects of PF-562,271 (a small-molecule inhibitor of FAK/PYK2) on (i) in vitro migration, invasion, and proliferation; (ii) tumor proliferation, invasion, and metastasis in a murine model; and (iii) stromal cell composition in the PDA microenvironment.

FAK regulates intestinal epithelial cell survival and proliferation during mucosal wound healing.

Background: Following damage to the intestinal epithelium, restoration of epithelial barrier integrity is triggered by a robust proliferative response. In other tissues, focal adhesion kinase (FAK) regulates many of the cellular processes that are critical for epithelial homeostasis and restitution, including cell migration, proliferation and survival. However, few studies to date have determined how FAK contributes to mucosal wound healing in vivo.

Matrix rigidity regulates cancer cell growth and cellular phenotype.

Background: The mechanical properties of the extracellular matrix have an important role in cell growth and differentiation. However, it is unclear as to what extent cancer cells respond to changes in the mechanical properties (rigidity/stiffness) of the microenvironment and how this response varies among cancer cell lines.

Methodology/principal Findings: In this study we used a recently developed 96-well plate system that arrays extracellular matrix-conjugated polyacrylamide gels that increase in stiffness by at least 50-fold across the plate.

FAK, PDZ-RhoGEF and ROCKII cooperate to regulate adhesion movement and trailing-edge retraction in fibroblasts.

A key step in cell migration is the dynamic formation and disassembly of adhesions at the front and the concomitant movement and release of adhesions in the rear of the cell. Fibroblasts maintained in the absence of serum have stable adhesions within the rear of the cell and exhibit reduced trailing-edge retraction resulting in an elongated cell phenotype. Addition of lysophosphatidic acid (LPA) induced the movement of adhesions and retraction of the trailing edge, thus mimicking tail retraction in a migrating cell.

Focal adhesion kinase as a regulator of cell tension in the progression of cancer.

Growing evidence indicates that critical steps in cancer progression such as cell adhesion, migration, and cell cycle progression are regulated by the composition and organization of the microenvironment. The adhesion of cancer cells to components of the microenvironment and the forces transmitted to the cells via the actinomyosin network and the signaling complexes organized within focal adhesions allow cancer cells to sense the local topography of the extracellular matrix and respond efficiently to proximal growth and migration promoting cues. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is over expressed in a variety of cancers and plays an important role in cell adhesion, migration, and anchorage-dependent growth.

Cellular characterization of a novel focal adhesion kinase inhibitor.

Focal adhesion kinase (FAK) is a member of a family of non-receptor protein-tyrosine kinases that regulates integrin and growth factor signaling pathways involved in cell migration, proliferation, and survival. FAK expression is increased in many cancers, including breast and prostate cancer. Here we describe perturbation of adhesion-mediated signaling with a FAK inhibitor, PF-573,228.

Focal adhesion kinase is required for the spatial organization of the leading edge in migrating cells.

The process of cell migration is initiated by protrusion at the leading edge of the cell, the formation of peripheral adhesions, the exertion of force on these adhesions, and finally the release of the adhesions at the rear of the cell. Focal adhesion kinase (FAK) is intimately involved in the regulation of this process, although the precise mechanism(s) whereby FAK regulates cell migration is unclear. We have used two approaches to reduce FAK expression in fibroblasts.

E-selectin and ICAM-1 are incorporated into detergent-insoluble membrane domains following clustering in endothelial cells.

Here we present data supporting the role of lipid rafts in endothelial cells during leukocyte adhesion. Following adhesion of THP-1 cells or antibody-mediated clustering, both E-selectin and intercellular adhesion molecule-1 (ICAM-1) partitioned into the detergent-insoluble portion of the endothelial cellular lysate. Sucrose gradient centrifugation revealed the partitioning of clustered E-selectin and ICAM-1 with the low-density fraction where they co-fractionated with src family kinases, markers of lipid rafts.

The Src-cortactin pathway is required for clustering of E-selectin and ICAM-1 in endothelial cells.

Adhesion molecules such as E-selectin and intercellular adhesion molecule-1 (ICAM-1) expressed on endothelial cells (ECs) at sites of inflammation play an important role in the recruitment of leukocytes from the bloodstream into extravascular tissue. However, little is known about the signaling pathways that are initiated in ECs following adhesion molecule engagement. Here, we report that an 85-kDa protein becomes tyrosine phosphorylated in human ECs following leukocyte adhesion or upon antibody-induced clustering of E-selectin or ICAM-1.