Foreword

Funding: European Research Council under the European Union’s Horizon 2020 Framework Programme (ERC StG ABLASE, 640012); BBSRC (BB/P027148/1); EPSRC Programme Grant (EP/P030017/1); EPSRC Doctoral Training Partnership (EP/N509759/1, EP/L505079/1).Mechanobiology plays a prominent role in cancer invasion and metastasis. The ability of a cancer to degrade extracellular matrix (ECM) is likely connected to its invasiveness. Many cancer cells form invadopodia—micrometer-sized cellular protrusions that promote invasion through matrix degradation (proteolysis). Although it has been hypothesized that invadopodia exert mechanical force that is implicated in cancer invasion, direct measurements remain elusive. Here, we use a recently developed interferometric force imaging technique that provides piconewton resolution to quantify invadopodial forces in cells of head and neck squamous carcinoma and to monitor their temporal dynamics. We compare the force exerted by individual protrusions to their ability to degrade ECM and investigate the mechanical effects of inhibiting invadopodia through overexpression of microRNA-375. By connecting the biophysical and biochemical characteristics of invadopodia, our study provides a new perspective on cancer invasion that, in the future, may help to identify biomechanical targets for cancer therapy.Publisher PDFPeer reviewe

Ab initio and finite-temperature molecular dynamics studies of lattice resistance in tantalum

This manuscript explores the apparent discrepancy between experimental data and theoretical calculations of the lattice resistance of bcc tantalum. We present the first results for the temperature dependence of the Peierls stress in this system and the first ab initio calculation of the zero-temperature Peierls stress to employ periodic boundary conditions, which are those best suited to the study of metallic systems at the electron-structure level. Our ab initio value for the Peierls stress is over five times larger than current extrapolations of experimental lattice resistance to zero-temperature. Although we do find that the common techniques for such extrapolation indeed tend to underestimate the zero-temperature limit, the amount of the underestimation which we observe is only 10-20%, leaving open the possibility that mechanisms other than the simple Peierls stress are important in controlling the process of low temperature slip.Comment: 12 pages and 9 figure

Macrosocial determinants of population health in the context of globalization

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55738/1/florey_globalization_2007.pd

Direct measurement of vertical forces shows correlation between mechanical activity and proteolytic ability of invadopodia

Mechanobiology plays a prominent role in cancer invasion and metastasis. The ability of a cancer to degrade extracellular matrix (ECM) is likely connected to its invasiveness. Many cancer cells form invadopodia—micrometer-sized cellular protrusions that promote invasion through matrix degradation (proteolysis). Although it has been hypothesized that invadopodia exert mechanical force that is implicated in cancer invasion, direct measurements remain elusive. Here, we use a recently developed interferometric force imaging technique that provides piconewton resolution to quantify invadopodial forces in cells of head and neck squamous carcinoma and to monitor their temporal dynamics. We compare the force exerted by individual protrusions to their ability to degrade ECM and investigate the mechanical effects of inhibiting invadopodia through overexpression of microRNA-375. By connecting the biophysical and biochemical characteristics of invadopodia, our study provides a new perspective on cancer invasion that, in the future, may help to identify biomechanical targets for cancer therapy

A positive feedback loop stabilizes the guanine-nucleotide exchange factor Cdc24 at sites of polarization.

In Saccharomyces cerevisiae, activation of Cdc42 by its guanine-nucleotide exchange factor Cdc24 triggers polarization of the actin cytoskeleton at bud emergence and in response to mating pheromones. The adaptor protein Bem1 localizes to sites of polarized growth where it interacts with Cdc42, Cdc24 and the PAK-like kinase Cla4. We have isolated Bem1 mutants (Bem1-m), which are specifically defective for binding to Cdc24. The mutations map within the conserved PB1 domain, which is necessary and sufficient to interact with the octicos peptide repeat (OPR) motif of Cdc24. Although Bem1-m mutant proteins localize normally, bem1-m cells are unable to maintain Cdc24 at sites of polarized growth. As a consequence, they are defective for apical bud growth and the formation of mating projections. Localization of Bem1 to the incipient bud site requires activated Cdc42, and conversely, expression of Cdc42-GTP is sufficient to accumulate Bem1 at the plasma membrane. Thus, our results suggest that Bem1 functions in a positive feedback loop: local activation of Cdc24 produces Cdc42-GTP, which recruits Bem1. In turn, Bem1 stabilizes Cdc24 at the site of polarization, leading to apical growth

Autocrine HBEGF expression promotes breast cancer intravasation, metastasis and macrophage-independent invasion in vivo

Increased expression of HBEGF in ER negative breast tumors is correlated with enhanced metastasis to distant organ sites and more rapid disease recurrence upon removal of the primary tumor. Our previous work has demonstrated a paracrine loop between breast cancer cells and macrophages in which the tumor cells are capable of stimulating macrophages through the secretion of CSF-1 while the tumor associated macrophages (TAMs) in turn aid in tumor cell invasion by secreting EGF. To determine how the autocrine expression of EGFR ligands by carcinoma cells would affect this paracrine loop mechanism, and in particular whether tumor cell invasion depends on spatial ligand gradients generated by TAMs, we generated cell lines with increased HBEGF expression. We find that autocrine HBEGF expression enhanced in vivo intravasation and metastasis, and resulted in a novel phenomenon in which macrophages were no longer required for in vivo invasion of breast cancer cells. In vitro studies revealed that expression of HBEGF enhanced invadopodium formation, thus providing a mechanism for cell autonomous invasion. The increased invadopodium formation was directly dependent on EGFR signaling, as demonstrated by a rapid decrease in invadopodia upon inhibition of autocrine HBEGF/EGFR signaling as well as inhibition of signaling downstream of EGFR activation. HBEGF expression also resulted in enhanced invadopodium function via upregulation of MMP2 and MMP9 expression. We conclude that high levels of HBEGF expression can short-circuit the tumor cell/macrophage paracrine invasion loop, resulting in enhanced tumor invasion that is independent of macrophage signaling

The EGF/CSF-1 Paracrine Invasion Loop Can Be Triggered by Heregulin beta 1 and CXCL12

An important step in the process of metastasis from the primary tumor is invasive spread into the surrounding stroma. Using an in vivo invasion assay, we have previously shown that imposed gradients of epidermal growth factor (EGF) or colony-stimulating factor-1 (CSF-1) can induce invasion through an EGF/CSF-1 paracrine loop between cancer cells and macrophages. We now report that invasion induced by other ligands also relies on this EGF/CSF-1 paracrine invasive loop. Using an in vivo invasion assay, we show that MTLn3 breast cancer cells overexpressing ErbB3 exhibit enhanced invasion compared with control MTLn3 cells in response to the ErbB3 ligand HRG-beta 1. The invasive response of both MTLn3-ErbB3 and transgenic MMTV-Neu tumors to HRG-beta 1 is inhibited by blocking EGF receptor, CSF-1 receptor, or macrophage function, indicating that invasiveness to HRG-beta 1 is dependent on the EGF/CSF-1 paracrine loop. Furthermore, we show that CXCL12 also triggers in vivo invasion of transgenic MMTV-PyMT tumors in an EGF/CSF-1-dependent manner. Although the invasion induced by HRG-beta 1 or CXCL12 is dependent on the EGF/CSF-1 paracrine loop, invasion induced by EGF is not dependent on HRG-beta 1 or CXCL12 signaling, showing an asymmetrical relationship between different ligand/receptor systems in driving invasion. Our results identify a stromal/tumor interaction that acts as an engine underlying invasion induced by multiple ligands. [Cancer lies 2009;69(7):3221-7