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. The key questions that we are addressing in our research on mechanisms of cancer metastasis are: 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 matrix composition and topology play in induction of invadopodia? 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. We established, using live-cell imaging, that dynamic invadopodia extend outward from cortactin cores. 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. Our goals are to understand the role of ECM in induction of invadopodia and to identify integrin-mediated signaling pathways that regulate invadopodia assembly and function in proteolytic degradation. We will be comparing findings using these arguably more physiological matrices to the conventional 2D gelatin-substrate system used widely to study molecular mechanisms driving invadopodia. 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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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
Koo, Hyun; Yamada, Kenneth M (2016) Dynamic cell-matrix interactions modulate microbial biofilm and tissue 3D microenvironments. Curr Opin Cell Biol 42:102-112
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
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
Sansing, Hope A; Sarkeshik, Ali; Yates, John R et al. (2011) Integrin ??1, ?v?, ?6? effectors p130Cas, Src and talin regulate carcinoma invasion and chemoresistance. Biochem Biophys Res Commun 406:171-6

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