Progression, and Tumor Maintenance

ABSTRACT Genetic changes required for the formation and progression of human Schwann cell tumors remain elusive. Using a Sleeping Beauty forward genetic screen, we identi-fi ed several genes involved in canonical Wnt signaling as potential drivers of benign neurofi bromas and malignant peripheral nerve sheath tumors (MPNSTs). In human neurofi bromas and MPNSTs, activation of Wnt signaling increased with tumor grade and was associated with downregulation of β-catenin destruction complex members or overexpression of a ligand that potentiates Wnt signaling, R-spondin 2 ( RSPO2). Induction of Wnt signaling was suffi cient to induce transformed properties in immortalized human Schwann cells, and downregulation of this pathway was suffi cient to reduce the tumorigenic phenotype of human MPNST cell lines. Small-molecule inhibition of Wnt signaling effectively reduced the viability of MPNST cell lines and synergistically induced apoptosis when combined with an mTOR inhibitor, RAD-001, suggesting that Wnt inhibition represents a novel target for therapeutic interven-tion in Schwann cell tumors. SIGNIFICANCE: We show canonical Wnt/β-catenin signaling is a novel genetic driver of Schwann cell tumor development and progression, due to downregulation of β-catenin destruction complex members and overexpression of RSPO2. Inhibitors of Wnt signaling alone, or in combination with RAD-001, may hav