[en] Tumor growth and relapse are often driven by cancer stem cells, but self-renewal mechanisms and genetic mutations that elevate their number are not fully understood. Here, we show that recurrent L122R mutation (Leucine to Argine change at amino acid 122) in the DNA-binding site of the Myogenic Differentiation 1 (MYOD1) transcription factor increases cancer stem cell frequency in aggressive Spindle cell/sclerosing rhabdomyosarcoma. MYOD1L122R also makes tumors resistant to chemotherapy and radiation. Epigenetic analysis reveals that MYOD1L122R binds MYC-like DNA recognition motifs to activate stem cell programs, while retaining some wild-type function to regulate muscle pathways that drive transformation. Mechanistically, MYOD1L122R transcriptionally activates Receptor tyrosine kinase-like Orphan Receptor 2 (ROR2) to turn on the non-canonical Wingless/Integrated (WNT) planar cell polarity pathway to increase both cancer stemness and therapy resistance. Targeting ROR2 with antibody-drug conjugates kills MYOD1L122R-mutated tumor cells, offering therapeutic opportunities. These findings provide insights into how MYOD1L122R rewires rhabdomyosarcoma to a stem-like state and defines a unique class of oncogenic transcription factors found in aggressive cancers.
Disciplines :
Genetics & genetic processes
Author, co-author :
Wei, Yun; Molecular Pathology Unit, Massachusetts General Research Institute, Harvard Medical School, Charlestown, MA, USA ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA ; Harvard Stem Cell Institute, Harvard Medical School, Cambridge, MA, USA
Corchete Sánchez, Luis Antonio ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA ; Broad Institute of MIT and Harvard, Cambridge, MA, USA
Mathavarajah, Sabateeshan; Molecular Pathology Unit, Massachusetts General Research Institute, Harvard Medical School, Charlestown, MA, USA ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA ; Harvard Stem Cell Institute, Harvard Medical School, Cambridge, MA, USA
Antelo, Diego; Molecular Pathology Unit, Massachusetts General Research Institute, Harvard Medical School, Charlestown, MA, USA ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA
Wang, Shuze; Molecular Pathology Unit, Massachusetts General Research Institute, Harvard Medical School, Charlestown, MA, USA ; Broad Institute of MIT and Harvard, Cambridge, MA, USA
Lee, Jihee; Molecular Pathology Unit, Massachusetts General Research Institute, Harvard Medical School, Charlestown, MA, USA ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA ; Harvard Stem Cell Institute, Harvard Medical School, Cambridge, MA, USA
Weissman, Alexander Daiki; Molecular Pathology Unit, Massachusetts General Research Institute, Harvard Medical School, Charlestown, MA, USA ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA
Kannambadi, Devika D; Molecular Pathology Unit, Massachusetts General Research Institute, Harvard Medical School, Charlestown, MA, USA ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA
Qin, Qian ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA ; Broad Institute of MIT and Harvard, Cambridge, MA, USA
Danielli, Sara G; Broad Institute of MIT and Harvard, Cambridge, MA, USA ; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA
Quantin, Elisa J; Molecular Pathology Unit, Massachusetts General Research Institute, Harvard Medical School, Charlestown, MA, USA ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA
Eng, Tiffany C; Molecular Pathology Unit, Massachusetts General Research Institute, Harvard Medical School, Charlestown, MA, USA ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA ; Harvard Stem Cell Institute, Harvard Medical School, Cambridge, MA, USA
Bacquelaine Veloso, Alexandra ; Université de Liège - ULiège > GIGA > GIGA Immunobiology - Hematology ; Molecular Pathology Unit, Massachusetts General Research Institute, Harvard Medical School, Charlestown, MA, USA ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA ; Harvard Stem Cell Institute, Harvard Medical School, Cambridge, MA, USA
Wang, Yueyang; Molecular Pathology Unit, Massachusetts General Research Institute, Harvard Medical School, Charlestown, MA, USA ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA ; Harvard Stem Cell Institute, Harvard Medical School, Cambridge, MA, USA
Neilsen, Gunnlaugur P; Center for Sarcoma and Connective Tissue Oncology, Department of Orthopedic Surgery, Massachusetts General Hospital, Boston, MA, USA
Yan, Chuan ; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
Yang, Valerie Shiwen; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore ; Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore ; Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore
Patel, Anand G ; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA ; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
Koo, Selene C ; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
Odeniyide, Patience; Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Pratilas, Christine A ; Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Rivera, Miguel N ; Molecular Pathology Unit, Massachusetts General Research Institute, Harvard Medical School, Charlestown, MA, USA ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA
Rheinbay, Esther; Molecular Pathology Unit, Massachusetts General Research Institute, Harvard Medical School, Charlestown, MA, USA. erheinbay@mgh.harvard.edu ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA. erheinbay@mgh.harvard.edu ; Broad Institute of MIT and Harvard, Cambridge, MA, USA. erheinbay@mgh.harvard.edu
Langenau, David M ; Molecular Pathology Unit, Massachusetts General Research Institute, Harvard Medical School, Charlestown, MA, USA. dlangenau@mgh.harvard.edu ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA. dlangenau@mgh.harvard.edu ; Harvard Stem Cell Institute, Harvard Medical School, Cambridge, MA, USA. dlangenau@mgh.harvard.edu
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