Abstract 3417: An in vivo functional screen to identify metastasis suppressor genes

Background When breast carcinomas remain confined to breast tissue, cure rates exceed 90% (http://seer.cancer.gov/csr/1975_2006/). However, if the cancer disseminates through the body, long-term survival decreases depending upon the extent of, and the sites of, colonisation Genes that control the different stages of the metastatic process need to be identified to better delineate the process, and to aid in the development of metastatic biomarkers and provide potential targets for the treatment of metastatic disease. Genetic screens, such as those that exploit RNA interference (RNAi), provide an unbiased approach to the identification of genes associated with a phenotype of interest. Although cell-based screens have been highly informative in identifying genes involved in tumour cell survival, migration and invasion, these in vitro approaches are largely unsuitable for interrogating the later stages of the metastatic process, in particular the processes of cell dissemination, tumour cell extravasation from the circulation and colonisation of secondary sites. Method Using the 4T1 mouse model an in vivo functional metastasis screen that integrates RNAi technology and massively parallel sequencing was implemented to rapidly discover and validate metastasis genes. Results Using this approach, 12 ‘hits’ that suppress tumour cell colonisation of the lungs were identified. 3 of the top 5 hits have been validated as novel metastasis suppressor genes in both mouse and human cell lines and further studies have been undertaken to elucidate the mechanism of action of the top hit. Critically, these findings are clinically relevant in primary breast cancers where there is a significant correlation between elevated expression levels of these suppressor genes and reduced frequency of metastatic events. Conclusion This study demonstrates the value of adopting an unbiased methodology to discover novel metastatic genes and establishes, for the first time, that an in vivo metastasis screen can be combined with next generation sequencing to identify novel components of the metastatic process. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3417. doi:1538-7445.AM2012-3417