The complex pattern of alterations in cell-matrix and cell-cell adhesion, migration, and associated signal transduction pathways that drive tumor cell invasion are insufficiently understood. In particular, the roles of membrane dynamics and integrins in these processes are not yet sufficiently clear. We are focusing on the following three facets of this problem that are relevant to both developmental and cancer cell migration. 1. How do invadopodia tiny cell surface structures mediating proteolysis initiate and function? What regulates their formation? 2. How are integrins and components of cell adhesions involved in tumor cell invasion and metastasis? 3. What roles does proteolytic degradation of the matrix play in 3D settings? We have developed new tools and approaches to address these questions. One approach has been to develop cutting-edge microscopy and novel invasion substrates, as well as to adapt TIRF (total internal reflection fluorescence) microscopy to study invadopodia. A second approach involves applying approaches used initially to characterize integrin functions in normal cells to elucidate molecular mechanisms of tumor metastasis. We previously published a description of the basic steps in the formation and function of invadopodia of tumor cells: the structural actin cores of invadopodia are formed first and then the protease MT1-MMP accumulates to mediate ECM degradation. Our new study has established, using live-cell imaging, that dynamic invadopodia extending outward from cortactin cores. Rapid high-resolution TIRF (total internal reflection fluorescence) microscopy has permitted imaging of the dynamic ventral cell membrane and cytoplasm in the closest proximity to the matrix substrate as invadopodia form. Invadopodium assembly was found to be initiated by docking of the cytoplasmic protein cortactin to the cell membrane adherent to extracellular matrix, associated with the formation of a distinctive invadopodial membrane process that extends towards the extracellular matrix. The tip of this invadopodial process flattens as it interacts with a 2D matrix, and it begins to undergo rapid ruffling and dynamic formation of filament-like protrusions as the invadopodium matures. Three distinct stages of invadopodium formation could be identified: the 1) invadopodial process stage, 2) invadopodial ruffle stage, and 3) mature invadopodia stage. This invadopodial complex with a cortactin-actin core and filamentous processes also exists in cells invading a 3D matrix, with dynamic filament-like invadopodia extending from the tip to interact with the collagen matrix. Thus, the invadopodium is a highly dynamic, filament-like extension of a complex micro-invasive structure. We are examining how invadopodia are induced during interactions with the extracellular matrix and the role of integrins in this process. We applied proteomics in a collaborative project involving Allison Berrier, a Hurricane Katrina Visiting Faculty Scholar in our laboratory who was supported by NIH and has since returned to Louisiana State University School of Dentistry in New Orleans. We collaborated with the proteomics mass spectrometry expert John Yates at The Scripps Research Institute and with J. Silvio Gutkind at NIDCR for initial characterization of integrin-associated adhesion components in well-characterized human oral carcinoma cell lines. We found specificity in the cytoplasmic proteins bound in different integrin adhesion complexes. Focusing on a few of these molecules, we found that p130Cas, Src, and talin function in oral carcinoma in vitro invasiveness and, surprisingly, also in resistance to the chemotherapeutic agent cisplatin. Interactions at the cell surface are likely to play important roles in many diseases. We are continuing a long-term collaboration with Subhash Dhawan in CBER, FDA to apply basic research approaches to characterize cell-surface and extracellular interactions involved in the pathogenesis of infectious diseases. Preliminary studies have identified novel roles for induction of endogenous cellular heme oxygenase-1 as a general inhibitor of infections by West Nile virus, dengue, poxvirus, and influenza. Selected aspects of these findings are being characterized in greater depth.

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National Institute of Dental & Craniofacial Research
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Xu, Derek Cui; Arthurton, Lewis; Baena-Lopez, Luis Alberto (2018) Learning on the Fly: The Interplay between Caspases and Cancer. Biomed Res Int 2018:5473180
Huang, Hanxia; Falgout, Barry; Takeda, Kazuyo et al. (2017) Nrf2-dependent induction of innate host defense via heme oxygenase-1 inhibits Zika virus replication. Virology 503:1-5
Huang, Hanxia; Konduru, Krishnamurthy; Solovena, Veronica et al. (2016) Therapeutic potential of the heme oxygenase-1 inducer hemin against Ebola virus infection. Curr Trends Immunol 17:117-123
Artym, Vira V (2016) Preparation of High-Density Fibrillar Collagen Matrices That Mimic Desmoplastic Tumor Stroma. Curr Protoc Cell Biol 70:10.19.1-10.19.11
Artym, Vira V (2016) Dense fibrillar collagen is a master activator of invadopodia. Mol Cell Oncol 3:e1035476
Koo, Hyun; Yamada, Kenneth M (2016) Dynamic cell-matrix interactions modulate microbial biofilm and tissue 3D microenvironments. Curr Opin Cell Biol 42:102-112
Takeda, Kazuyo; Adhikari, Rewati; Yamada, Kenneth M et al. (2015) Hemin activation of innate cellular response blocks human immunodeficiency virus type-1-induced osteoclastogenesis. Biochem Biophys Res Commun 464:7-12
Bacot, Silvia M; Feldman, Gerald M; Yamada, Kenneth M et al. (2015) Pathogenic prion protein fragment (PrP106-126) promotes human immunodeficiency virus type-1 infection in peripheral blood monocyte-derived macrophages. Virology 476:372-6
Meseda, Clement A; Srinivasan, Kumar; Wise, Jasen et al. (2014) Non-coding RNAs and heme oxygenase-1 in vaccinia virus infection. Biochem Biophys Res Commun 454:84-8
Zhou, Zhao-Hua; Kumari, Namita; Nekhai, Sergei et al. (2013) Heme oxygenase-1 induction alters chemokine regulation and ameliorates human immunodeficiency virus-type-1 infection in lipopolysaccharide-stimulated macrophages. Biochem Biophys Res Commun 435:373-7

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