Disordered Regulation of Wnt/beta-catenin Signaling in MPNST Development and Maintenance

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DESCRIPTION (provided by applicant): 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.