Identifying Novel Tumor Suppressor Genes in a Unique Model of Robust In Vivo Tumor Suppression

Elsa Pardee Foundation Grant Application Project Description Planarians are fascinating organisms with vast, untapped potential to become an excellent model for discovering mechanisms with immediate relevance to cancer. Adult planarians maintain a large, heterogeneous population of multi and pluripotent stem cells that endow them with two remarkable abilities: 1) the constant maintenance of homeostasis (i.e. immortality) and 2) the regeneration of entirely new worms — perfectly repatterned and reproportioned — from small pieces of amputated tissue. Yet, despite maintaining this large population of highly-plastic, proliferating stem cells, these animals do not exhibit obvious signs of cancer. This feat is even more impressive considering that planarians live in aquatic environments that are rich in mutagenic agents. These worms must therefore possess robust mechanisms that protect their genome stability and tissue integrity, both normally and in response to genotoxic stress. To identify specific genes and mechanisms that enable these animals to avoid and/or suppress tumorigenesis, we will look for those genomic loci in the planarian genome bearing a highly conserved chromatin signature found at tumor-suppressor genes. We will then exploit the high-throughput power of RNAi screening in planarians to determine which of the identified candidate genes show in vivo function as tumor-suppressors, i.e. lead to abnormal increases in cell proliferation, migration, and/or invasion. These studies have the potential to uncover many new genes, pathways, and mechanisms that operate in vivo to protect tissue integrity. Funding for this project will allow us to quickly identify those genes, form testable hypotheses about their role in tumor-suppression, and design experiments to test their functional conservation.