Metastasis, the spread of cancer cells from a primary tumor to distant sites, proceeds via separation of individual cells from the tumor, subsequent invasion into the endothelium, entry into the bloodstream, and eventual insertion and growth at a secondary site. Growth factors circulating through the bloodstream beckon tumor cells from the parental site, an inherently spatially driven process. Signaling pathways have evolved so that cells can respond to their environment and many of these pathways possess pronounced spatiotemporal properties as well. In short, the classic view of a biochemical response to an environmental stimulus, namely a linear series of enzyme catalyzed reactions, does not always adequately explain the underlying behavior of cells. Indeed, the now emerging view of cell signaling posits that cell behavior is not only dependent upon which pathway is activated, but by when, where, and which other pathways are activated as well. A series of wavelength-distinct light-activatable signaling proteins will be constructed to explore the intracellular biochemical and cell wide migratory consequences of spatially localized protein activity. In addition, these covalently modified protein constructs will be used to examine the synergistic influence of multiple signaling pathways as a function of time and space on migratory aptitude. Finally, we will address the validity of an emerging model of metastatic potential.
The overriding goal of this research program is to delineate the spatiotemporal role played by signaling pathways that drive the early stages of metastasis. Elucidation of the underlying mechanisms responsible for invasiveness potential could ultimately serve as the basis for new therapeutic strategies for the treatment of metastatic disease.
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|Wang, Qunzhao; Priestman, Melanie A; Lawrence, David S (2013) Monitoring of protein arginine deiminase activity by using fluorescence quenching: multicolor visualization of citrullination. Angew Chem Int Ed Engl 52:2323-5|