The major scientific focus of my laboratory is to determine the Ras-initiated signaling pathways and their relevant transcriptional targets that contribute to human epithelial cell transformation and metastasis. Ras is mutated in approximately one quarter of all human cancers with the highest incidence in pancreatic, lung, colon, and thyroid tumors. In addition, there is considerable experimental evidence that persistent upstream signaling in other epithelial cancers may activate Ras. Because multiple autocrine or paracrine growth factor pathways contribute to the transformation of epithelial cells and their colonization of distant tissues during the development of metastasis, Ras signaling pathways are expected to provide broadly applicable diagnostic markers and therapeutic targets. Multiple downstream effectors mediate Ras signaling, and there is a growing appreciation that the signaling outcomes of Ras activation demonstrate species and cell context differences. We have shown that ectopic Ras activation leads to the new expression of a bone metastatic phenotype in the DU145 xenograft model of human prostate cancer, and furthermore, that bone tropism can be mediated by a specific Ras effector pathway. We have investigated the role of signaling pathways initiated by oncogenic Ras including Raf/ERK, PI3-kinase, and Ral guanine nucleotide exchange factors (RalGEFs), in stimulating tissue-specific experimental metastasis of DU145. Although the RalGEF pathway appears to be required for Ras-initiated tumorigenesis in human epithelial cells, a role in metastasis has not been addressed. Oncogenic Ras promoted metastasis of hematogenously delivered DU145 to multiple organs including bone, brain, and other soft tissues. Activation of the Raf/ERK pathway stimulated metastatic colonization of the brain, while activation of the RalGEF pathway led to bone metastases, the most common organ site for prostate cancer. Enhanced anchorage-independent growth was a cell biological correlate of bone, but not brain, metastasis. Ras-mediated signaling did not appear to influence the osteolytic properties of DU145. These data begin to identify signaling pathways relevant for organ-specific metastasis. There are very few models of metastatic prostate cancer, and our DU145 model is unique in that the initiating genetic event, i.e. Ras activation, can be manipulated. The DU145(Ras) system provides an experimental system for the identification of genes mediating metastasis to different organs. It also provides an efficient and predictable model system of tissue-specific metastases for preclinical testing of therapeutic agents.
| Oberst, Michael D; Beberman, Stacey J; Zhao, Liu et al. (2008) TDAG51 is an ERK signaling target that opposes ERK-mediated HME16C mammary epithelial cell transformation. BMC Cancer 8:189 |
| Ward, Y; Spinelli, B; Quon, M J et al. (2004) Phosphorylation of critical serine residues in Gem separates cytoskeletal reorganization from down-regulation of calcium channel activity. Mol Cell Biol 24:651-61 |
