TY - JOUR
T1 - Canonical Wnt/β-catenin signaling drives human schwann cell transformation, progression, and tumor maintenance
AU - Watson, Adrienne L.
AU - Rahrmann, Eric P.
AU - Moriarity, Branden S.
AU - Choi, Kwangmin
AU - Conboy, Caitlin B.
AU - Greeley, Andrew D.
AU - Halfond, Amanda L.
AU - Anderson, Leah K.
AU - Wahl, Brian R.
AU - Keng, Vincent W.
AU - Rizzardi, Anthony E.
AU - Forster, Colleen L.
AU - Collins, Margaret H.
AU - Sarver, Aaron L.
AU - Wallace, Margaret R.
AU - Schmechel, Stephen C.
AU - Ratner, Nancy
AU - Largaespada, David A.
PY - 2013/6
Y1 - 2013/6
N2 - 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. 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 neurofibromas.
AB - 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. 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 neurofibromas.
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UR - http://www.scopus.com/inward/citedby.url?scp=84878868657&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-13-0081
DO - 10.1158/2159-8290.CD-13-0081
M3 - Article
C2 - 23535903
AN - SCOPUS:84878868657
SN - 2159-8290
VL - 3
SP - 675
EP - 689
JO - Cancer Discovery
JF - Cancer Discovery
IS - 6
ER -
