Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma.
Embryonal rhabdomyosarcoma (ERMS) is a common pediatric malignancy of muscle, with relapse being the major clinical challenge. Self-renewing tumor-propagating cells (TPCs) drive cancer relapse and are confined to a molecularly definable subset of ERMS cells. To identify drugs that suppress ERMS self-renewal and induce differentiation of TPCs, a large-scale chemical screen was completed. Glycogen synthase kinase 3 (GSK3) inhibitors were identified as potent suppressors of ERMS growth through inhibiting proliferation and inducing terminal differentiation of TPCs into myosin-expressing cells. In support of GSK3 inhibitors functioning through activation of the canonical WNT/β-catenin pathway, recombinant WNT3A and stabilized β-catenin also enhanced terminal differentiation of human ERMS cells. Treatment of ERMS-bearing zebrafish with GSK3 inhibitors activated the WNT/β-catenin pathway, resulting in suppressed ERMS growth, depleted TPCs, and diminished self-renewal capacity in vivo. Activation of the canonical WNT/β-catenin pathway also significantly reduced self-renewal of human ERMS, indicating a conserved function for this pathway in modulating ERMS self-renewal. In total, we have identified an unconventional tumor suppressive role for the canonical WNT/β-catenin pathway in regulating self-renewal of ERMS and revealed therapeutic strategies to target differentiation of TPCs in ERMS.
Departments of Pathology and Regenerative Medicine and the Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114.
Eleanor Y
EY
Chen
Michael T
MT
DeRan
Myron S
MS
Ignatius
Kathryn Brooke
KB
Grandinetti
Ryan
R
Clagg
Karin M
KM
McCarthy
Riadh M
RM
Lobbardi
Jillian
J
Brockmann
Charles
C
Keller
Xu
X
Wu
David M
DM
Langenau
D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D018233:Rhabdomyosarcoma, Embryonal / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D015027:Zebrafish; D051176:beta Catenin / Q000378:metabolism*
D004791:Enzyme Inhibitors; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3