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

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

Author information

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: dlangenau@mgh.harvard.edu.

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

PMID:
28614716
PMCID:
PMC5563075
DOI:
10.1016/j.celrep.2017.05.061
[Indexed for MEDLINE]
Free PMC Article

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