Cell-cell and cell-matrix interactions.

In this year's annual ASCB Meeting Minisymposium on Cell–Cell and Cell–Matrix Interactions, new data were presented on several aspects of the biology of cell adhesions. The role of cell adhesions in cancer was the topic of three of the talks, two of which were focused on identifying how invasion is affected by cell–matrix and cell–cell adhesions. Yasmin Moshfegh from Louis Hodgson's lab (Albert Einstein College of Medicine) presented data showing a role for Rac1 in invadopodia formation, one of the initial steps in tumor cell invasion. The data showed that Rac1 suppresses invadopodia formation, and by using a fluorescence resonance energy transfer (FRET)-based Rac biosensor, the researchers showed that Rac1 activity is suppressed at sites of invadopodia formation. They further linked this to Rac1-mediated activation of PAK1, which in turn led to cortactin phosphorylation and invadopodia disassembly. Thomas Marshall (winner of the MBoC Paper of the Year Award) from Jody Rosenblatt's lab (Huntsman Cancer Institute) presented data on how APC (adenomatous polyposis coli) protein regulates the directionality of cell extrusion and how this could contribute to tumor cell metastasis in colon cancer, in which APC is frequently mutated. Cells with normal APC mainly extrude to the apical side of the tissue, whereas mutant APC reverses this directionality. The researchers also showed that the C-terminal domain of APC regulated this directionality. APC lacking this domain led to basal protrusion of the cancer cells, perhaps contributing to tumor cell invasion to basal layers. Taru Muranen from Joan Brugge's lab (Harvard Medical School) presented data on how extracellular matrix contact mediates drug resistance in tumor cells, wherein only matrix-attached cancer cells up-regulate a protective response (including anti-apoptotic Bcl-2 family proteins) in response to drug treatment, leading to cancer cell survival. In the other half of the Minisymposium, the speakers took a more mechanistic approach toward research on cell–matrix interactions. Viola Vogel (ETH Zurich) presented recent work on probes and new assays that demonstrate how cells exploit fibronectin fibrils as mechanochemical signal converters. She also presented proteomic data–derived evidence that extracellular phosphorylation and phosphorylated proteins are physiologically far more important than previously thought and are associated particularly with diseased tissues, such as those found in cancer. Michael Rubashkin from Valerie Weaver's lab (University of California–San Francisco) presented recent work on the development of a novel microscopy technique—scanning angle interference microscopy (SAIM)—that allows the study of focal adhesion structures in live cells at the nanoscale. SAIM was used to study how the relative position of vinculin changes in response to traction forces and how myosin contractility affects this localization. The researchers utilized vinculin activity mutants to study this and showed that active vinculin positions itself closer to the cell surface. This localization was also reflected in the structure of focal adhesions, suggesting that the relative position of vinculin corresponds to different adhesions. Caitlin Collins from Ellie Tzima's lab (University of North Carolina at Chapel Hill) reported on the role of the mechanosensory molecule PECAM-1 in endothelial mechanotransduction. The approach the researchers took was to use magnetic tweezers to apply tensional forces on PECAM-1 magnetic beads. On application of mechanical force on PECAM-1, they observed integrin and phosphatidylinositol 3-kinase pathway activation, both of which were required for adaptive stiffening of the endothelial cells. They further showed that this pathway led to global activation of RhoA and global formation of focal adhesions in endothelial cells. This pathway could have implications in vivo for atherosclerotic plaque formation, in which there is stiffening of the endothelial cells, and PECAM-1 could be employed to elicit some of the early events leading to plaque formation.