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 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.

Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation

“…The Sleeping Beauty system and pathway analysis defined mutations predicting loss of Gsk3β and Arid1b, identifying the WNT and STAT pathways as players that might cooperate with loss of Nf1 in neurofibromagenesis (Figure 1). GSK3β and β- catenin signaling were previously implicated in MPNST, sarcomas that are malignant derivatives of neurofibromas (Mo et al, 2013; Rahrmann et al, 2013; Watson et al, 2013). Other CIS genes ( WAPAL , SP3 , BTBD9 , and IGFR1 ) are up-regulated in neurofibroma cells, suggesting roles as proto-oncogenes early in tumor progression.…”

“…B-catenin is a developmental signaling pathway re-activated in many cancers. How β-catenin becomes elevated and if β-catenin plays a role in neurofibroma is unknown, although neurofibroma β-catenin expression was reported (Luscan et al, 2014; Mo et al, 2013; Watson et al, 2013). Supporting possible roles for β-catenin in nerve tumorigenesis, in vivo activation of β-catenin in developing SCs delays SC differentiation and results in sustained proliferation (Grigoryan et al, 2013).…”

Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types

“…Ectopic expression of Rspo2 was shown to increase tumorigenic and invasive properties of mouse breast cell lines (25). Genomic rearrangements and transcriptional activation in human tumors that result in elevated RSPO expression have been identified, suggesting that RSPO may be functionally important for tumor development (29)(30)(31)(32). However, no direct demonstration of a functional role for RSPO in cancer development and maintenance has been reported to date.…”

Individual roles of p53 and NF1 in OPC Competition and Gliomagenesis

“…These malignant tumors are the result of neurofibromas becoming deadly and thus serve as a perfect system for comparing changes between benign and malignant states. In these patients, they found that the Wnt pathway was gradually up regulated as malignancy increased (Watson et al, 2013).…”

“…While the loss of one would promote proliferation, the loss of the other would lead to reduced differentiation, thereby loss of both cooperatively lead to tumor formation ( Figure 1.4 in Chapter 1). In addition to in vivo analysis, we also purified both pre-transforming mutant OPCs (Pre-T OPCs) and malignant tumor cells using the OPC-specific surface marker PDGFRα, then examined the activities of commonly studied signaling nodes (Cadinu et al, 2014;Gorgoulis et al, 2005;Maglietta et al, 2012;Watson et al, 2013). Since NF1 is known as a RasGAP (Klose et al, 1998;Morcos et al, 1996;Scheffzek et al, 1998;Shin et al, 2012), we focused on analyzing the downstream effectors of the Ras pathway in this study, specifically on the progressive activation of these molecules from pre-malignant to malignant stages.…”