Metastasis is the single most clinically important step in oncogenic progression, yet the underlying molecular events remain poorly understood. This proposal involves study of two proteins, RhoC and Coactosin, which are consistently upregulated in metastasis across a variety of cancers, with the goal of testing the hypothesis that these proteins act synergistically to promote tumor cell motility and metastasis. My studies will focus on the role of these two proteins in the invasive and mestatatic properties of melanomas, will give insight into actin dynamics in metastasis, and will provide clues about how to pursue pharmacological strategies to target metastasis. RhoC is a small GTPase that is upregulated in, and is necessary for, metastasis, but its mechanism of action remains unclear. RhoC function will be examined in melanoma cells lines with genetically altered RhoC levels, specifically with a panel of motility and invasion assays that will reveal how RhoC alters cell behavior. In addition, pharmacological and genetic manipulation of two key downstream effectors of RhoC (ROCK and mDia) will be utilized to determine which signaling functions are important for RhoC effects on motility and metastasis. Coactosin is an actin-binding protein whose biological function remains unclear. Data from its Dictyostelium homologue suggest it may inhibit capping of actin filaments, while its homology to Cofilin suggests it may have an effect on actin filament turnover. These functions are similar to those performed by RhoC effector pathways, leading to the hypothesis that Coactosin functions coordinately with RhoC to increase cell motility and invasion. To test this hypothesis, in vitro biochemical assays will be used to test these mechanisms of Coactosin activity, and genetic manipulation in cell biological assays will be utilized to determine the role of Coactosin in melanoma tumor cell motility and metastasis. Taken together, our studies will help elucidate the role of aberrant actin dynamics in metastasis and may validate the signaling pathways involving RhoC and Coactosin for melanoma treatment.
The mobility of metastatic cells increases the potential complications of cancer by affecting the functions of distant organs, and also complicates treatment since surgery to remove the cancer becomes much more difficult, if not impossible. Proteins that are consistently expressed at higher levels in multiple types of metastatic cancer hold considerable promise as potential therapeutic targets, and this proposal is designed to characterize two such proteins: RhoC and Coactosin. ? ? ?
| Roadcap, David W; Clemen, Christoph S; Bear, James E (2008) The role of mammalian coronins in development and disease. Subcell Biochem 48:124-35 |
