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
Affiliations
Myron S. Ignatius
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Madeline N. Hayes
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Riadh Lobbardi
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Eleanor Y. Chen
Department of Pathology, University of Washington, Seattle, WA 98195, USA
Karin M. McCarthy
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Prethish Sreenivas
Greehey Children’s Cancer Research Institute and Department of Molecular Medicine, UT Health Sciences Center, San Antonio, TX 78229, USA
Zainab Motala
Division of Hematology/Oncology, Hospital for Sick Children and Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada
Adam D. Durbin
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Aleksey Molodtsov
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Sophia Reeder
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Alexander Jin
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Sivasish Sindiri
Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Brian C. Beleyea
Department of Pediatrics and Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
Deepak Bhere
Molecular Neurotherapy and Imaging Laboratory, Stem Cell Therapeutics and Imaging Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Matthew S. Alexander
Department of Pediatrics and Genetics, Children’s of Alabama and the University of Alabama at Birmingham, Birmingham, AL 35233, USA
Khalid Shah
Department of Pediatrics and Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
Charles Keller
Children’s Cancer Therapy Development Institute, Beaverton, OR 97005, USA
Corinne M. Linardic
Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Petur G. Nielsen
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
David Malkin
Division of Hematology/Oncology, Hospital for Sick Children and Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada
Javed Khan
Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
David M. Langenau
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
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.
