title: Canonical Wnt/β-catenin signaling drives human schwann cell transformation, 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 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 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 sufficient to induce transformed properties in immortalized human Schwann cells, and downregulation of this pathway was sufficient 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 intervention in Schwann cell tumors.
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis,MN 55455, USA.
authors.forename: Adrienne L
authors.initials: AL
authors.lastname: Watson
authors.forename: Eric P
authors.initials: EP
authors.lastname: Rahrmann
authors.forename: Branden S
authors.initials: BS
authors.lastname: Moriarity
authors.forename: Kwangmin
authors.initials: K
authors.lastname: Choi
authors.forename: Caitlin B
authors.initials: CB
authors.lastname: Conboy
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Greeley
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Halfond
authors.forename: Leah K
authors.initials: LK
authors.lastname: Anderson
authors.forename: Brian R
authors.initials: BR
authors.lastname: Wahl
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Keng
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Rizzardi
authors.forename: Colleen L
authors.initials: CL
authors.lastname: Forster
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Collins
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sarver
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wallace
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Schmechel
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D015536:Down-Regulation; D006801:Humans; D051379:Mice; D018317:Nerve Sheath Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology*; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin
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