Cell invasion across basement membranes is a driving force behind cell dispersal and organ formationduring normal development, but also is used by metastatic cancer cells. The mechanisms used by cells toinvade remain poorly understood. Therefore, elucidating the mechanisms that mediate cell invasion ismedically significant. Cell invasion is a multi-step process that involves: 1) attachment of the invading cell tothe basement membrane, 2) removal of the basement membrane, and 3) migration through the basementmembrane. SPARC is an extracellular matrix (ECM) protein that has multiple functions in development andis 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.mayfunction to alter the basement membrane or other ECM proteins to promote AC invasion. This suggests anew mechanism by which SPARC facilitates metastasis during cancer progression by fostering invasionacross basement membranes in cells that would normally be incapable of invasion. C. elegans is a simplemodel 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 requirementsof SPARC in fostering AC invasion, 2) determining if SPARC promotes invasion by altering the basementmembrane and ECM proteins, and 3) testing whether SPARC functions in the AC and regulates theexpression 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. Thiswill 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 cancerouscells exploit these same mechanisms in order to metastasize although these mechanisms are poorlyunderstood. The ECM protein SPARC is overexpressed in numerous metastatic cancers and our preliminaryresearch suggests SPARC fosters cell invasion in the nematode worm Caenorhabditis elegans, whichshares molecular and cellular basement membrane aspects of invasive metastatic cancer cells.
The aim ofthis work is to elucidate the mechanism(s) underlying the ability of SPARC to promote cell invasion, whichwill likely lead to the development of more effective strategies to treat cancer.
