Social Bonds of Female Baboons Enhance Infant Survival

It has proven difficult to systematically study the genetic basis of metastasis with the currently available techniques. The Drosophila system described here circumvents the complication of acquired background mutations, which can occur through repeated passaging of cell lines or during the typically long latent period of mammalian tumor progression. In our initial screen, we found that mutations in different genes affecting the same physiological process— epithelial cell polarity maintenance—are sufficient in combination with Ras V12 to promote metastatic behavior in vivo. Interestingly, later stage human cancers typically lose cell polarity markers and epithelial structure during epithelial to mesenchymal transition (31). Also, E-cadherin loss, basement membrane degradation, and induction of cell migration and invasion relate well to observations made in human metastasis (15, 31, 32), which suggests that the ongoing screen will uncover genes and general mechanisms relevant to malignancy in humans. It has been proposed that oncogenes such as Ras may play a dual role in tumorigenesis and metastasis (33); however, this has not yet been rigorously proven in mammalian systems, as the effects of Ras in cell culture depend greatly on the particular cell line used. We provide experimental evidence that genetic alterations promoting noninvasive tumor growth can indeed make additional contributions to the development of metastatic behavior, as RasV12 expression is a crucial factor in making cell polarity– deficient cells metastasize. Furthermore, we show that oncogenic Ras specifically cooperates with inactivation of cell polarity genes to promote metastatic behavior. This may provide an explanation for the different metastatic potential observed in tumors of distinctive origins. The Drosophila genetics techniques described here should make it easier to analyze the specific targets of RasV12 in metastatic cells, to identify other genes that cooperate with Ras V12 or other oncogenic alterations in promoting metastasis, and to elucidate the cellular processes that go awry during metastatic progression.