Our major research goals in this project are to characterize the roles of cellular interactions and signal transduction in pathogenesis. One major focus is on tumor cell invasion and metastasis, with a goal of identifying novel molecular regulators and mediators. A fundamental question in cancer biology is the relationship of the local matrix environment to cancer progression. For example, a common feature of advanced carcinomas is the induction of a dense collagenous matrix surrounding tumors during the process of desmoplasia. After completing studies establishing the role of dense fibrillar collagen in induction of proteolytically active invadopodia, we have turned to the question of how alterations in the physical rigidity of the matrix substrate can alter the nature of cell migration by a variety of human tumor cell lines. For quantifying a variety of parameters of cell migration, a non-biased, automated computer-based system termed FastTracks was developed and has been applied to a detailed analysis of the capacity of various human tumor cells to undergo migration toward regions of increased substrate or matrix stiffness, a biological process termed durotaxis. Human cancer cell lines from fibrosarcoma, breast carcinoma, and glioblastoma all migrate preferentially towards stiffer regions of a stiffness gradient, analogous to normal human fibroblasts. Interestingly, the most efficient migration occurs when cells initiate migration from a soft, relatively compliant substrate. Tumor cell invasiveness may be promoted by epithelial-mesenchymal transition (EMT). In studies of normal tissue morphogenesis, we have been characterizing the novel regulator Btbd7 as an inducer of the EMT transcription factor Snail2 and a disruptor of E-cadherin mediated cell-cell adhesion. We are currently evaluating whether Btbd7 or fibronectin, its upstream extracellular matrix regulator, can play a role in the invasiveness of certain tumor cells. Tumor expansion can be influenced by multiple factors, including immune cells. A joint collaborative study with the laboratory of Dr. Alberto Baena at Oxford is evaluating the interplay between Drosophila tumors and immune cells, with particular focus on the roles of caspases. Molecular interactions at the cell surface with soluble or matrix factors are likely to play important roles in many diseases. We have continued a long-term collaboration with Dr. Subhash Dhawan in CBER, FDA to characterize cell-surface and extracellular interactions involved in the pathogenesis or suppression of infectious diseases, with particular focus on the protective role of a host cellular response to extracellularly provided hemin, an inducer of heme oxygenase-1 (HO-1). Because we have extensive expertise in real-time imaging of cell behavior in vitro and in organ explants, we have a joint research collaboration with Dr. Ashok Kulkarni's laboratory to use the GCaMP6 mouse system for direct visualization of calcium signaling. Current research is focused on the regulatory kinase Cdk5 in characterizing and comparing pain signaling and mechano-sensation in the mouse trigeminal ganglion.
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