The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma

Myron S. Ignatius; Madeline N. Hayes; Riadh Lobbardi; Eleanor Y. Chen; Karin M. McCarthy; Prethish Sreenivas; Zainab Motala; Adam D. Durbin; Aleksey Molodtsov; Sophia Reeder; Alexander Jin; Sivasish Sindiri; Brian C. Beleyea; Deepak Bhere; Matthew S. Alexander; Khalid Shah; Charles Keller; Corinne M. Linardic; Petur G. Nielsen; David Malkin; Javed Khan; David M. Langenau

doi:10.1016/j.celrep.2017.05.061

The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma

Myron S. Ignatius, Madeline N. Hayes, Riadh Lobbardi, Eleanor Y. Chen, Karin M. McCarthy, Prethish Sreenivas, Zainab Motala, Adam D. Durbin, Aleksey Molodtsov, Sophia Reeder, Alexander Jin, Sivasish Sindiri, Brian C. Beleyea, Deepak Bhere, Matthew S. Alexander, Khalid Shah, Charles Keller, Corinne M. Linardic, Petur G. Nielsen, David MalkinJaved Khan, David M. Langenau

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

Abstract

Tumor-propagating cells (TPCs) share self-renewal properties with normal stem cells and drive continued tumor growth. However, mechanisms regulating TPC self-renewal are largely unknown, especially in embryonal rhabdomyosarcoma (ERMS)—a common pediatric cancer of muscle. Here, we used a zebrafish transgenic model of ERMS to identify a role for intracellular NOTCH1 (ICN1) in increasing TPCs by 23-fold. ICN1 expanded TPCs by enabling the de-differentiation of zebrafish ERMS cells into self-renewing myf5+ TPCs, breaking the rigid differentiation hierarchies reported in normal muscle. ICN1 also had conserved roles in regulating human ERMS self-renewal and growth. Mechanistically, ICN1 upregulated expression of SNAIL1, a transcriptional repressor, to increase TPC number in human ERMS and to block muscle differentiation through suppressing MEF2C, a myogenic differentiation transcription factor. Our data implicate the NOTCH1/SNAI1/MEF2C signaling axis as a major determinant of TPC self-renewal and differentiation in ERMS, raising hope of therapeutically targeting this pathway in the future.

Original language	English (US)
Pages (from-to)	2304-2318
Number of pages	15
Journal	Cell Reports
Volume	19
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2017.05.061
State	Published - Jun 13 2017

Keywords

MEF2C
NOTCH1
SNAI1
de-differentiation
muscle
rhabdomyosarcoma
self-renewal
tumor propagating cells
zebrafish

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2017.05.061

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Ignatius, M. S., Hayes, M. N., Lobbardi, R., Chen, E. Y., McCarthy, K. M., Sreenivas, P., Motala, Z., Durbin, A. D., Molodtsov, A., Reeder, S., Jin, A., Sindiri, S., Beleyea, B. C., Bhere, D., Alexander, M. S., Shah, K., Keller, C., Linardic, C. M., Nielsen, P. G., ... Langenau, D. M. (2017). The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma. Cell Reports, 19(11), 2304-2318. https://doi.org/10.1016/j.celrep.2017.05.061

Ignatius, MS, Hayes, MN, Lobbardi, R, Chen, EY, McCarthy, KM, Sreenivas, P, Motala, Z, Durbin, AD, Molodtsov, A, Reeder, S, Jin, A, Sindiri, S, Beleyea, BC, Bhere, D, Alexander, MS, Shah, K, Keller, C, Linardic, CM, Nielsen, PG, Malkin, D, Khan, J & Langenau, DM 2017, 'The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma', Cell Reports, vol. 19, no. 11, pp. 2304-2318. https://doi.org/10.1016/j.celrep.2017.05.061

@article{8e3bf96e7c8b4ba485a7c5c3dd06afc2,

title = "The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma",

abstract = "Tumor-propagating cells (TPCs) share self-renewal properties with normal stem cells and drive continued tumor growth. However, mechanisms regulating TPC self-renewal are largely unknown, especially in embryonal rhabdomyosarcoma (ERMS)—a common pediatric cancer of muscle. Here, we used a zebrafish transgenic model of ERMS to identify a role for intracellular NOTCH1 (ICN1) in increasing TPCs by 23-fold. ICN1 expanded TPCs by enabling the de-differentiation of zebrafish ERMS cells into self-renewing myf5+ TPCs, breaking the rigid differentiation hierarchies reported in normal muscle. ICN1 also had conserved roles in regulating human ERMS self-renewal and growth. Mechanistically, ICN1 upregulated expression of SNAIL1, a transcriptional repressor, to increase TPC number in human ERMS and to block muscle differentiation through suppressing MEF2C, a myogenic differentiation transcription factor. Our data implicate the NOTCH1/SNAI1/MEF2C signaling axis as a major determinant of TPC self-renewal and differentiation in ERMS, raising hope of therapeutically targeting this pathway in the future.",

keywords = "MEF2C, NOTCH1, SNAI1, de-differentiation, muscle, rhabdomyosarcoma, self-renewal, tumor propagating cells, zebrafish",

author = "Ignatius, {Myron S.} and Hayes, {Madeline N.} and Riadh Lobbardi and Chen, {Eleanor Y.} and McCarthy, {Karin M.} and Prethish Sreenivas and Zainab Motala and Durbin, {Adam D.} and Aleksey Molodtsov and Sophia Reeder and Alexander Jin and Sivasish Sindiri and Beleyea, {Brian C.} and Deepak Bhere and Alexander, {Matthew S.} and Khalid Shah and Charles Keller and Linardic, {Corinne M.} and Nielsen, {Petur G.} and David Malkin and Javed Khan and Langenau, {David M.}",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s)",

year = "2017",

month = jun,

day = "13",

doi = "10.1016/j.celrep.2017.05.061",

language = "English (US)",

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AU - Ignatius, Myron S.

AU - Hayes, Madeline N.

AU - Lobbardi, Riadh

AU - Chen, Eleanor Y.

AU - McCarthy, Karin M.

AU - Sreenivas, Prethish

AU - Motala, Zainab

AU - Durbin, Adam D.

AU - Molodtsov, Aleksey

AU - Reeder, Sophia

AU - Jin, Alexander

AU - Sindiri, Sivasish

AU - Beleyea, Brian C.

AU - Bhere, Deepak

AU - Alexander, Matthew S.

AU - Shah, Khalid

AU - Keller, Charles

AU - Linardic, Corinne M.

AU - Nielsen, Petur G.

AU - Malkin, David

AU - Khan, Javed

AU - Langenau, David M.

PY - 2017/6/13

Y1 - 2017/6/13

N2 - Tumor-propagating cells (TPCs) share self-renewal properties with normal stem cells and drive continued tumor growth. However, mechanisms regulating TPC self-renewal are largely unknown, especially in embryonal rhabdomyosarcoma (ERMS)—a common pediatric cancer of muscle. Here, we used a zebrafish transgenic model of ERMS to identify a role for intracellular NOTCH1 (ICN1) in increasing TPCs by 23-fold. ICN1 expanded TPCs by enabling the de-differentiation of zebrafish ERMS cells into self-renewing myf5+ TPCs, breaking the rigid differentiation hierarchies reported in normal muscle. ICN1 also had conserved roles in regulating human ERMS self-renewal and growth. Mechanistically, ICN1 upregulated expression of SNAIL1, a transcriptional repressor, to increase TPC number in human ERMS and to block muscle differentiation through suppressing MEF2C, a myogenic differentiation transcription factor. Our data implicate the NOTCH1/SNAI1/MEF2C signaling axis as a major determinant of TPC self-renewal and differentiation in ERMS, raising hope of therapeutically targeting this pathway in the future.

AB - Tumor-propagating cells (TPCs) share self-renewal properties with normal stem cells and drive continued tumor growth. However, mechanisms regulating TPC self-renewal are largely unknown, especially in embryonal rhabdomyosarcoma (ERMS)—a common pediatric cancer of muscle. Here, we used a zebrafish transgenic model of ERMS to identify a role for intracellular NOTCH1 (ICN1) in increasing TPCs by 23-fold. ICN1 expanded TPCs by enabling the de-differentiation of zebrafish ERMS cells into self-renewing myf5+ TPCs, breaking the rigid differentiation hierarchies reported in normal muscle. ICN1 also had conserved roles in regulating human ERMS self-renewal and growth. Mechanistically, ICN1 upregulated expression of SNAIL1, a transcriptional repressor, to increase TPC number in human ERMS and to block muscle differentiation through suppressing MEF2C, a myogenic differentiation transcription factor. Our data implicate the NOTCH1/SNAI1/MEF2C signaling axis as a major determinant of TPC self-renewal and differentiation in ERMS, raising hope of therapeutically targeting this pathway in the future.

KW - MEF2C

KW - NOTCH1

KW - SNAI1

KW - de-differentiation

KW - muscle

KW - rhabdomyosarcoma

KW - self-renewal

KW - tumor propagating cells

KW - zebrafish

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SN - 2211-1247

VL - 19

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JO - Cell Reports

JF - Cell Reports

IS - 11

ER -

The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma

Abstract

Keywords

ASJC Scopus subject areas

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