Cell invasion across basement membranes is a driving force behind cell dispersal and organ formation during normal development, but also is used by metastatic cancer cells. The mechanisms used by cells to invade remain poorly understood. Therefore, elucidating the mechanisms that mediate cell invasion is medically significant. Cell invasion is a multi-step process that involves: 1) attachment of the invading cell to the basement membrane, 2) removal of the basement membrane, and 3) migration through the basement membrane. SPARC is an extracellular matrix (ECM) protein that has multiple functions in development and is overexpressed in a number of metastatic cancers. We have discovered that SPARC promotes anchor cell (AC) invasion across basement membranes in Caenorhabditis elegans. We hypothesize that SPARC.may function to alter the basement membrane or other ECM proteins to promote AC invasion. This suggests a new mechanism by which SPARC facilitates metastasis during cancer progression by fostering invasion across basement membranes in cells that would normally be incapable of invasion. C. elegans is a simple model system allowing for a detailed, in vivo analysis to study the ability of SPARC to promote cell invasion. This proposal will investigate the role of SPARC by 1) identifying the temporal and functional requirements of SPARC in fostering AC invasion, 2) determining if SPARC promotes invasion by altering the basement membrane and ECM proteins, and 3) testing whether SPARC functions in the AC and regulates the expression of AC target genes. A combination of approaches will be used including RNA interference, AC- specific promoters, time-lapse analysis, fluorescence-labeling experiments, and immunohistochemistry. This will allow for a deeper understanding into the function of SPARC in cell invasion and basement membranes, and will provide the candidate with new training in ECM biology, advanced microscopy, and cell biology. Relevance to public health: Not only are cell invasion events needed for proper development, but cancerous cells exploit these same mechanisms in order to metastasize although these mechanisms are poorly understood. The ECM protein SPARC is overexpressed in numerous metastatic cancers and our preliminary research suggests SPARC fosters cell invasion in the nematode worm Caenorhabditis elegans, which shares molecular and cellular basement membrane aspects of invasive metastatic cancer cells.
The aim of this work is to elucidate the mechanism(s) underlying the ability of SPARC to promote cell invasion, which will likely lead to the development of more effective strategies to treat cancer. ? ? ?
