Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma

Eleanor Y. Chen, Michael T. DeRan, Myron S. Ignatius, Kathryn Brooke Grandinetti, Ryan Clagg, Karin M. McCarthy, Riadh M. Lobbardi, Jillian Brockmann, Charles Keller, Xu Wu, David M. Langenau

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Abstract

Embryonal rhabdomyosarcoma (ERMS) is a common pediatric malignancy of muscle, with relapse being the major clinical challenge. Selfrenewing 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 screenwas 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, recombinantWNT3A 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 selfrenewal 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 canonicalWNT/ β-catenin pathway in regulating self-renewal of ERMS and revealed therapeutic strategies to target differentiation of TPCs in ERMS.

Original languageEnglish (US)
Pages (from-to)5349-5354
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number14
DOIs
StatePublished - 2014

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Embryonal Rhabdomyosarcoma
Glycogen Synthase Kinase 3
Catenins
Growth
Neoplasms
Recurrence
Zebrafish
Myosins

ASJC Scopus subject areas

  • General

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Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma. / Chen, Eleanor Y.; DeRan, Michael T.; Ignatius, Myron S.; Brooke Grandinetti, Kathryn; Clagg, Ryan; McCarthy, Karin M.; Lobbardi, Riadh M.; Brockmann, Jillian; Keller, Charles; Wu, Xu; Langenau, David M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 14, 2014, p. 5349-5354.

Research output: Contribution to journalArticle

Chen, EY, DeRan, MT, Ignatius, MS, Brooke Grandinetti, K, Clagg, R, McCarthy, KM, Lobbardi, RM, Brockmann, J, Keller, C, Wu, X & Langenau, DM 2014, 'Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 14, pp. 5349-5354. https://doi.org/10.1073/pnas.1317731111
Chen, Eleanor Y. ; DeRan, Michael T. ; Ignatius, Myron S. ; Brooke Grandinetti, Kathryn ; Clagg, Ryan ; McCarthy, Karin M. ; Lobbardi, Riadh M. ; Brockmann, Jillian ; Keller, Charles ; Wu, Xu ; Langenau, David M. / Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 14. pp. 5349-5354.
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AU - Brooke Grandinetti, Kathryn

AU - Clagg, Ryan

AU - McCarthy, Karin M.

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AU - Wu, Xu

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AB - Embryonal rhabdomyosarcoma (ERMS) is a common pediatric malignancy of muscle, with relapse being the major clinical challenge. Selfrenewing 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 screenwas 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, recombinantWNT3A 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 selfrenewal 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 canonicalWNT/ β-catenin pathway in regulating self-renewal of ERMS and revealed therapeutic strategies to target differentiation of TPCs in ERMS.

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