We carried out two large screens to identify genes driving MPNST formation or maintenance: 1) An shRNA screen in human MPNST cell lines, and 2) a Sleeping Beauty (SB) transposon- based insertional mutagenesis screen in a mouse model of MPNST. Both research approaches identified Wnt/?atenin-regulated pathways as critical mediators of MPNST maintenance. Preliminary data confirms that the Wnt/?atenin pathway is required for MPNST maintenance and can be targeted using small molecules. Remarkably, we identified multiple mechanisms of activation of ?atenin that operate in MPNST. Our proposal focuses on these. Aim 1 is based on our data demonstrating that genetic or pharmacological activation of the ?atenin destruction complex reduce ?atenin levels, reduce target gene expression, and inhibit cell survival and proliferation in MPNST. Aim 2 is based on data showing that some MPNSTs ectopically express a Wnt/?atenin activator R-spondin 2 (RSPO2) due to transcript fusion with the upstream EIF3E gene, a mechanism we recently identified in human colorectal cancer. Aim 3 is based on data revealing that the ?atenin target gene PITX2 plays a critical role in MPNST cell survival. Our goals are two-fold: to define the molecular landscape of ?atenin de- regulation in MPNST, and perform a thorough pre-clinical evaluation of critical targets for intervention in the Wnt/?atenin pathway in MPNST, setting the stage for effective clinical testing in human patients. The Co-PIs have established a successful collaborative relationship built on complementary skills and resources. Abundant and orthogonal preliminary data support the basic hypothesis of this proposal.