A major research goal of this project is to characterize the roles of cell interactions with the extracellular matrix in tumor 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. However, whether this increase in collagen is protective against tumor expansion or actually contributes to cancer pathogenesis was not well characterized. Micro-invasive structures termed invadopodia can mediate local proteolytic degradation of matrix to permit tumor cell invasion. We hypothesized that the dense accumulations of extracellular matrix found in advanced human tumors during the desmosplastic response might alter the formation of invadopodia. One approach was to produce thin, cell-free 3D sections of human tumor tissue extracellular matrix for comparisons with adjacent normal tissue matrix; such human tumor matrices induced invadopodia. A second approach has been to generate an artificial matrix that could functionally mimic this dense desmoplastic matrix. Centrifugation of collagen gels could generate a novel high-density fibrillar collagen (HDFC) matrix, which was as potent in inducing invadopodia as human tumor matrix. It was active even in the absence of serum factors. Surprisingly, HDFC was equally effective for induction of matrix-degrading invadopodia in non-transformed primary human dermal fibroblasts in the absence of serum, and this effect was suppressed by serum. We are currently characterizing and quantifying 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. Tumor cell invasiveness may be promoted by epithelial-mesenchymal transition (EMT). In studies of normal tissue morphogenesis, we identified 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 invasiveness by certain tumor cells, and whether abnormal elevation of Btbd7 levels can induce normal epithelial cells to become invasive. Molecular interactions at the cell surface with soluble or matrix factors are likely to play important roles in many diseases. We have been involved in 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. Some molecules are found to enhance infectivity, while others can suppress this process. For example, the host cellular response to extracellularly provided hemin, an inducer of heme oxygenase-1 (HO-1), elicits host protective responses against viral infections including HIV and poxvirus. This collaborative project has recently been extended to explore the potential of inducing HO-1 mediated host responses to help suppress Ebola and Zika virus infection. Since hemin is an FDA-approved drug, its induction of HO-1 might provide a potential general host-defense therapeutic strategy against a variety of pathogens. Bacterial infections associated with biofilm formation are often tenacious and difficult to eradicate. We have compared the literature on bacterial biofilms with studies of mammalian extracellular matrices. Although there are obvious differences in molecular composition between these two classes of matrix, there are striking similarities in roles for structural and biologically functional extracellular matrix molecules in organizing cell populations and modulating intracellular functions. For example, both types of extracellular matrix can establish local regions of heterogeneity of composition, density, and stiffness that can lead to local differences in pH, hypoxia, and other biologically important modulators of cell responses to the local microenvironment. We suggest that applying sophisticated approaches and new techniques from each field to the other can help to accelerate research into both biofilms and pathological mammalian matrices.
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