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Canonical Wnt/B-Catenin Signaling Drives Human Schwann Cell Transformation, Progression, and Tumor Maintenance

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Canonical Wnt/B-Catenin Signaling Drives Human Schwann Cell Transformation, Progression, and Tumor Maintenance Published OnlineFirst March 27, 2013; DOI: 10.1158/2159-8290.CD-13-0081 RESEARCH ARTICLE Canonical Wnt/b-catenin Signaling Drives Human Schwann Cell Transformation, Progression, and Tumor Maintenance Adrienne L. Watson 1,2,4,5, Eric P. Rahrmann 1,2,4,5, Branden S. Moriarity 1,2,4,5, Kwangmin Choi 8,10, Caitlin B. Conboy 1, Andrew D. Greeley 1,2, Amanda L. Halfond 6, Leah K. Anderson 2, Brian R. Wahl 2, Vincent W. Keng 1,2,4,5,13, Anthony E. Rizzardi 3,12, Colleen L. Forster 7, Margaret H. Collins9,10, Aaron L. Sarver 1, Margaret R. Wallace 11, Stephen C. Schmechel 3,7,12, Nancy Ratner 8,10, and David A. Largaespada 1,2,4,5,6 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst March 27, 2013; DOI: 10.1158/2159-8290.CD-13-0081 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 have therapeutic value for patients with MPNSTs or neurofi bromas. Cancer Discov; 3(6); 674–89. ©2013 AACR. See related commentary by Reilly, p. 610. INTRODUCTION It is known that biallelic loss of the Neurofi bromin 1 gene ( NF1 ) in Schwann cells is the pathologic cause of the benign Malignant peripheral nerve sheath tumors (MPNSTs) are neurofi bromas seen in NF1 patients, but secondary genetic soft tissue sarcomas that are believed to originate in the changes, many of which remain unknown, must occur for these Schwann cell or Schwann cell precursors ( 1 ). These tumors can benign tumors to transform into MPNSTs ( 1 , 5–8 ). Ten percent occur in the context of Neurofi bromatosis Type 1 syndrome of NF1-associated neurofi bromas will undergo malignant trans- (NF1), which occurs in 1 in 3,000 live births, but can also occur formation, the leading cause of death in adult NF1 patients spontaneously in the general population ( 2, 3 ). Because of the ( 4, 5 ). MPNSTs can also form spontaneously, in the absence of incomplete understanding of the genes and pathways driving NF1 loss, and the genes responsible for spontaneous MPNST MPNST development and progression, the current treatment formation are also largely unknown ( 3, 4 ). Loss of PTEN expres- for patients is surgical resection of the tumor, if possible, fol- sion and overexpression of EGF receptor (EGFR) are 2 changes lowed by nonspecifi c, high-dose chemotherapy ( 4, 5 ). These often seen in both spontaneous MPNSTs and NF1-associated therapies often prove ineffective, and subsequently, patients MPNSTs, but there are likely many other important genetic with MPNSTs suffer very poor 5-year survival rates of less than changes and signaling pathways yet to be identifi ed ( 5 , 8–14 ). 25% ( 3, 4 ). This shows the urgent need for a more complete Canonical Wnt/β-catenin signaling has been shown to play a understanding of the genetic events that drive these tumors, to role in many types of cancer, including colorectal, lung, breast, develop novel targeted therapies to treat these patients. ovarian, prostate, liver, and brain tumors ( 15 ). However, this pathway has not been directly implicated in neurofi bromas or Authors’ Affi liations: 1Masonic Cancer Center, Departments of 2Genetics, Cell MPNSTs. In other cell types, Wnt signaling can be activated Biology and Development and 3Laboratory Medicine and Pathology, 4Center in cancer through a variety of mechanisms, including activat- for Genome Engineering, 5 Brain Tumor Program, 6Health and Natural Sciences ing mutations in β-catenin ( CTNNB1 ), overexpression of Wnt Department, 7 BioNet, Academic Health Center, University of Minnesota, Min- 8 ligand genes, inactivating mutations in AXIN1 , GSK3B , and neapolis, Minnesota; Divisions of Experimental Hematology and Cancer Biol- β ogy and 9Pathology and Laboratory Medicine, 10Department of Pediatrics, APC (all encoding members of the -catenin destruction com- Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; 11Department of plex), and promoter hypermethylation of negative regulators Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida; of Wnt signaling ( 16 ). Another mechanism of Wnt pathway 12Department of Pathology, University of Washington, Seattle, Washington, activation recently shown in colorectal cancer is overexpres- 13 USA; Department of Applied Biology and Chemical Technology, The Hong sion of R-spondins due to gene fusions ( 17 ). R-spondins are Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong secreted ligands that can potentiate Wnt signaling in the Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). presence of Wnt ligands ( 18 ). Wnt signaling can also be acti- vated via crosstalk with other signaling pathways, including Corresponding Author: David A. Largaespada, University of Minnesota, Genetics, Cell Biology, and Development, 6-160 Jackson, 321 Church Street the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway, SE, Minneapolis, MN 55455. Phone: 612-626-4979; Fax: 612-625-4648; where loss of PTEN can activate PKB/AKT, causing the phos- E-mail: [email protected] phorylation and inactivation of GSK3B, which results in doi: 10.1158/2159-8290.CD-13-0081 stabilization of β-catenin protein ( 19 ). Growth factor signal- © 2013 American Association for Cancer Research. ing pathways can also activate Wnt signaling, such as in the JUNE 2013CANCER DISCOVERY | 675 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst March 27, 2013; DOI: 10.1158/2159-8290.CD-13-0081 RESEARCH ARTICLE Watson et al. case of stimulation of the EGF receptor (EGFR), which results insertion site (CIS)-associated gene list was generated independ- in the activation of β-catenin/T-cell factor (TCF)/lymphoid ently for benign neurofi bromas and MPNSTs, as diagnosed enhancer factor (LEF)–dependent transcription of genes such by histopathologic examination (Rahrmann and colleagues, as CyclinD1 (CCND1 ), C-Myc (MYC ), and Survivin (BIRC5 ) submitted for publication). We required that integrations map ( 20, 21 ). Notably, some human MPNSTs have been shown to uniquely to the murine genome with a sequence length that have loss of PTEN expression and/or express high levels of would preclude random mapping. Furthermore, we required active EGFR ( 9 , 11 , 12 , 14 ). β-catenin–dependent transcrip- that each integration be present at more than 1 of 10,000 of tion can promote progression through the cell cycle, stem the total sequences present to exclude potential non-driver cell self-renewal, and epithelial to mesenchymal transition, mutations that are found in minor subclones or due to artifacts all of which play a role in tumor initiation and progression ( 31 ). When the entire CIS gene list for MPNSTs was analyzed ( 15, 16 , 22 ). Because of the importance of this pathway in driv- using Ingenuity Pathway Analysis (Ingenuity Systems, www. ing tumorigenesis in many types of cancer, the development of ingenuity.com ), we found enrichment for genes that are present small-molecule inhibitors that target Wnt signaling is rapidly in the Wnt/β-catenin pathway ( P = 3.93E-4). Furthermore, underway and has the potential for profound clinical benefi ts when immunohistochemical (IHC) analysis was conducted on for patients with Wnt-driven tumors ( 16 , 23 , 24 ). murine tumors from this SB screen at various stages of progres- We have implicated canonical Wnt signaling in the develop- sion, the level and nuclear localization of β-catenin increased ment and progression of peripheral nerve tumors by using with tumor progression ( Fig. 1A ). In addition to tumors from a murine Sleeping Beauty ( SB ) forward genetic screen (25). In mice induced with SB , 4 other well-established mouse models of addition, we show that several well-established murine models MPNST showed nuclear β-catenin expression ( Fig. 1B ; refs. 13, of neurofi bromas and MPNST development also exhibit activa- 14 , 32–34 ). These mouse models represent both NF1-associated tion of the Wnt signaling pathway. Activation of this pathway and sporadic MPNST development by a variety of genetic has been confi rmed in human patient samples by gene expres- mechanisms. Interestingly, tumors
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