Cancer metastasis is one of the most poorly understood phases of cancer progression, in part because of the heterogeneity of metastasizing cells and the complexity of the tissues they invade. We propose that planarian flatworms, which possess a large, heterogeneous population of in vivo stem cells, can be developed into an excellent model for discovering fundamental molecular mechanisms with immediate relevance to metastatic cancer. Not only do planarians appear to have an intrinsic resistance to tumorigenesis, but they also demonstrate a robust resistance to genotoxic stress upon exposure to gamma-radiation. However, the planarian response to other types of genotoxic stress, e.g. chemotherapies, has not been thoroughly investigated. We will 1) analyze the response of in vivo planarian stem cells to multiple types of genotoxic stress, including chemo and radiation therapies, 2) compare these responses in two related planarian species, and 3) use forward genetics (via RNAi) to screen for epigenetic regulators that are critical to the planarian response to genotoxic stress. These experiments will both establish planarians as a model for studying the functional effects of genotoxic stress on dynamic, in vivo, stem cells and also identify epigenetic regulators that likely serve important
roles in genome and organismal protection. The results from this pilot study will generate the preliminary data needed to apply for an R01 (or similar) grant.