| The majority of fatalities in cancer patients are not due to the growth of primary tumors, but rather the ability of late stage tumors to spread to new locations during a complex process called metastasis. Despite years of research, the molecular events underlying metastasis remain poorly understood. To bypass some of the problems inherent in current models for metastasis, we have developed a Drosophila model to systematically screen for genetic alterations sufficient to induce the in vivo metastatic behavior of otherwise noninvasive tumors.; From this screen, we found that the combination of oncogenic Ras expression and inactivation of any one of a number of Drosophila cell polarity genes, including scribble, lethal giant larvae, discs large, stardust, bazooka, and cdc42, produce metastatic features observed in malignant human tumors, including basement membrane degradation, loss of E-cadherin expression, induction of cell migration and invasion, and the formation of distant growths.; We tested the ability of scrib mutations to cause Drosophila overgrowths induced by means other than Ras V12 to metastasize; however, the ability of scrib mutants to cause this phenotype depended upon the presence of the RasV12 allele. This indicates that increased proliferation, growth, and survival by means other than RasV12 are not sufficient to cause the metastatic progression of scrib -/- cells, indicating that oncogenic Ras plays a direct role in promoting metastasis. Our results further show that the Ras-dependent metastatic signal is likely mediated through a dual activation of the MAPK and PI3K signaling pathways. Together, these results provide experimental evidence that genetic alterations promoting noninvasive tumor growth can indeed make additional contributions to the development of metastatic behavior. This may also provide an explanation for the different metastatic potential observed in tumors of distinctive origins.; It will be greatly informative using the advantages of this Drosophila genetic model to analyze the specific targets of RasV12 in metastatic cells, to identify other genes that cooperate with RasV12 or other oncogenic alterations in promoting metastasis, and to further elucidate the cellular processes that go awry during metastatic progression. |
