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Title: Canonical Wnt/β-catenin signaling drives human schwann cell transformation, progression, and tumor maintenance
Authors: Watson, AL
Rahrmann, EP
Moriarity, BS
Choi, K
Conboy, CB
Greeley, AD
Halfond, BS
Anderson, LK
Wahl, BR
Keng, VW 
Rizzardi, AE
Forster, CL
Collins, MH
Sarver, AL
Wallace, MR
Schmechel, SC
Ratner, N
Largaespada, DA
Keywords: Malignant peripheral nerve sheath tumors
Schwann cells
Neurofibromatosis type 1 syndrome
Neurofibromin 1
Neurofibromatosis 1
Wnt signaling
Targeted therapies
Sleeping Beauty transposon system
Forward genetic screen
Murine models
Issue Date: 2013
Publisher: American Association for Cancer Research
Source: Cancer discovery, 2013, v. 3, no. 6, p. 674-689 How to cite?
Journal: Cancer discovery
Abstract: Genetic changes required for the formation and progression of human Schwann cell tumors remain elusive. Using a Sleeping Beauty forward genetic screen, we identified several genes involved in canonical Wnt signaling as potential drivers of benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). In human neurofibromas and MPNSTs, activation of Wnt signaling increased with tumor grade and was associated with down-regulation of β-catenin destruction complex members or overexpression of a ligand that potentiates Wnt signaling, R-spondin 2 (RSPO2). Induction of Wnt signaling was sufficient to induce transformed properties to immortalized human Schwann cells, and down-regulation of this pathway was sufficient to reduce the tumorigenic phenotype of human MPNST cell lines. Small molecule inhibition of Wnt signaling effectively reduced 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 intervention in Schwann cell tumors.
ISSN: 2159-8274 (print)
2159-8290 (online)
DOI: 10.1158/2159-8290.CD-13-0081.
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