Abstract
Metastasis accounts for over 90% of cancer death, but its mechanisms are still poorly understood. One valuable approach that has been commonly used to study metastasis was to compare paired poorly and highly metastatic cell lines, either for roles of a few genes of interest or global gene expression differences. Our work involved in using shRNA screen to identify global key functional differences between these matched cell lines. We postulated that the distinct in vivo phenotypes of these paired cell lines are a consequence of alterations in their cellular signaling networks during tumor progression. To characterize these functional differences, we performed arrayed shRNA screens against the human kinome to examine kinase requirements for survival and proliferation on several pairs of melanoma, colon or prostate cancer cell lines. From these screens, we have identified a set of kinases that become essential for multiple highly metastatic cells, some of which have been linked to metastasis (such as c‐Met) but more have not. Several of these genes were shown to be amplified or mutated in human cancers. In vivo metastatic experiments are underway to prioritize these kinases by evaluating which kinases can promote metastasis when ectopically expressed. Since inhibition of these kinases phenocopied c‐Met inhibition, we also sought to test if any of these kinases are functionally linked to c‐Met signaling. Indeed, several of the identified kinases became essential when immortalized melanocytes were made tumorigenic and metastatic by introduction of activated c‐Met. Biochemical and genetic rescue experiments are currently ongoing to further examine the links between these genes and c‐Met. These studies offer new insights into the cellular signaling pathways operating in metastatic cancer cells and also suggest potential targets to treat metastatic cancers.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A200.