| Program Leader: K. Green, PhD |
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Program Co-Leader: C. LaBonne, PhD |
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The Tumor Invasion, Metastasis, and Angiogenesis (TIMA) Program of the Robert H. Lurie Comprehensive Cancer Center is a well-established research program that remains focused on multidisciplinary basic and translational research. The TIMA Program includes both basic research and clinical scientists with the common goal of providing a more detailed understanding of the individual cellular and molecular processes that underlie metastatic disease. Kathy Green, PhD, and Carole LaBonne, PhD, are the leaders of this interdepartmental program that includes 32 faculty from 11 departments and 3 schools. Between January 2001 and September 2006 there have been 344 cancer-relevant publications from the current program members. Eighty-four (24%) of these publications represent intra-programmatic collaborations and 63 (18%) represent inter-programmatic collaborations. Total current cancer-relevant peer-reviewed funding is $8,654,549 (direct) with $2,198,208 (direct) from NCI and $6,456,341 (direct) from other peer-reviewed sources. Specific areas of research focus include the regulation of cell adhesion and adhesion receptor signaling, investigation of matrix assembly and proteolytic remodeling of the stromal microenvironment, elucidation of the mechanisms that control epithelial-mesenchymal transitions, cell motility, and invasiveness, and characterization of the mechanisms that regulate tumor angiogenesis. Program members are highly interactive both intra- and inter-programmatically, participating in a number of joint basic and translational research initiatives. As the vast majority of cancer patient mortality is attributable to metastatic disease, the overall objective of the TIMA program is to obtain a more detailed understanding of these fundamental processes, and to translate these findings into the clinical setting as novel diagnostic or therapeutic approaches for the inhibition of tumor metastasis and angiogenesis.
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Modulation of cell-cell and cell-matrix contacts is a prerequisite for a metastasizing tumor cell to escape the normal tissue confines, acquire a motile phenotype, penetrate connective tissue barriers, and establish metastases. Researchers in this group are examining mechanisms of cell-cell and cell-matrix adhesion, the assembly/disassembly of these adhesive complexes, and how activation of adhesion-induced signaling pathways impacts gene expression and cellular behavior. A major research focus is directed toward understanding mechanisms for normal and aberrant assembly, disassembly, and stabilization of cell-cell and cell-matrix junctions (Beitel, Chenn, Gottardi, Green, Jones, Kansas, Wang). Coordination of cell adhesion with changes in gene expression and elucidation of the contribution of adhesion receptor signaling to tissue-specific metastasis is a second focus of active investigation (Chenn, Gottardi, Green, Jones, LaBonne, Lamm, Stack).
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Deposition and remodeling of extracellular matrix (ECM) components impacts both cell adhesion signaling and motility and functions as a mechanism to provide key epigenetic cues from the tumor stromal microenvironment. Research in this group is focused on ECM structure and assembly, matrix proteolysis, and the functional consequences of matrix modifications to wound healing and tumor biology. A multidisciplinary approach involving cell imaging, model organism studies and bioengineering of unique 3-dimensional scaffolds is used to understand matrix structure and tumor fibrosis (Jones, Kramer, Munshi, Mustoe, Shea, Varga). A related research focus on matrix proteolysis and its impact on adhesion signaling probes the role of the tumor microenvironment in determination of tumor cell fate (Hendrix, Khalkhali-Ellis, Munshi, Paller, Seftor, Stack, XQ Wang).
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Migration is an essential component of normal developmental processes; However, acquisition of a motile phenotype is a key requirement for both hematogenous and intraperitoneal metastasis as well as for tumor neovascularization. This group is comprised of researchers who study the fundamental process of cell movement; the biological, biochemical and biophysical structures that contribute to a motile phenotype; and regulation of cellular migration. Research is focused on analysis of molecular motor structure and function and cytoskeletal assembly (Gelfand, Goldman, Rice). Additional investigators utilize a variety of approaches employing model organisms, metastatic tumor cells, and tumor cell-endothelial cell interactions to elucidate the cellular signaling pathways that contribute to acquisition of invasiveness (Chenn, Chew, Jones, LaBonne, Stack).
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Acquisition of a vascular supply enables tumors to procure nutrients necessary for continued growth and provides an avenue of escape for metastasizing tumor cells. Conversely, angiogenesis inhibition has provided a promising new target for novel therapeutic approaches to shrink primary tumor size and prevent metastasis. Research in the vascular biology group is focused on basic research on tube formation, endothelial cell survival and hypoxia response (Beitel, Chandel, Chew, Kibbe, Mustoe, Schnaper, Schumacher). Translational studies investigate both mechanistic and therapeutic analysis of novel proteins with anti-angiogenic properties and the role of the immune response in aberrant vasculogenesis (Awad, Crawford, Dean, Gonzalez, Kramer, Volpert).
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