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

Cell Rep. 2017 Jun 13;19(11):2304-2318. doi: 10.1016/j.celrep.2017.05.061.

Authors

Myron S Ignatius¹, Madeline N Hayes², Riadh Lobbardi², Eleanor Y Chen³, Karin M McCarthy⁴, Prethish Sreenivas⁵, Zainab Motala⁶, Adam D Durbin⁷, Aleksey Molodtsov⁴, Sophia Reeder⁴, Alexander Jin⁴, Sivasish Sindiri⁸, Brian C Beleyea⁹, Deepak Bhere¹⁰, Matthew S Alexander¹¹, Khalid Shah⁹, Charles Keller¹², Corinne M Linardic⁸, Petur G Nielsen¹³, David Malkin⁶, Javed Khan⁸, David M Langenau¹⁴

Affiliations

¹ Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Stem Cell Institute, Boston, MA 02114, USA; Greehey Children's Cancer Research Institute and Department of Molecular Medicine, UT Health Sciences Center, San Antonio, TX 78229, USA.
² Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Stem Cell Institute, Boston, MA 02114, USA.
³ Department of Pathology, University of Washington, Seattle, WA 98195, USA.
⁴ Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Greehey Children's Cancer Research Institute and Department of Molecular Medicine, UT Health Sciences Center, San Antonio, TX 78229, USA.
⁶ Division of Hematology/Oncology, Hospital for Sick Children and Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
⁷ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA.
⁸ Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
⁹ Department of Pediatrics and Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
¹⁰ Molecular Neurotherapy and Imaging Laboratory, Stem Cell Therapeutics and Imaging Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹¹ Department of Pediatrics and Genetics, Children's of Alabama and the University of Alabama at Birmingham, Birmingham, AL 35233, USA.
¹² Children's Cancer Therapy Development Institute, Beaverton, OR 97005, USA.
¹³ Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA.
¹⁴ Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Stem Cell Institute, Boston, MA 02114, USA. Electronic address: [email protected].

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.

MeSH terms

Animals
Cell Differentiation / physiology
Humans
MEF2 Transcription Factors / metabolism*
Receptor, Notch1 / metabolism*
Rhabdomyosarcoma, Embryonal / metabolism*
Rhabdomyosarcoma, Embryonal / pathology
Signal Transduction
Snail Family Transcription Factors / metabolism*
Transcription Factors / metabolism
Xenopus Proteins / metabolism
Zebrafish

Substances

MEF2 Transcription Factors
MEF2C protein, human
NOTCH1 protein, human
Receptor, Notch1
SNAI1 protein, human
Snai1 protein, Xenopus
Snail Family Transcription Factors
Transcription Factors
Xenopus Proteins

Abstract

MeSH terms

Substances

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