Currenlty, the genes which must be expressed for tumor cells to metastasize are unknown. This project is designed to identify such genes through a two-pronged approach. In the first part, DNA from metastatic cells will be transfected into non- metastatic cells. Metastases will be selected in nude mice. The ability to transfer the metastatic capacity will allow the cloning of the transferred genes. In the second part, we will exploit our finding that the Adenovirus ElA gene, when introduced in some metastatic cells, will suppress their metastatic ability. This reduction in metastatic potential correlates with a significant reduction in type IV collagenase secretion. The suppressive effect of AdE1A on metastasis will serve as a tool to allow the identification of genes involved in metastasis. The various pleomorphic actions of AdE1A have been separated by mutational analysis and these mutants will be used to determine which also suppress metastasis. Then differential cDNA cloning will be used to isolate those genes whose transcription is affected by AdE1A. Further biochemical characterization will determine which features associated with metastatic cells are altered by AdE1A. Thus, both approaches, that of gene transfer and of analysis of the inhibitory effect of AdE1A on metastasis, should allow the cloning of genes directly involved in metastasis.
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