title: CD133+brain tumor-initiating cells are dependent on STAT3 signaling to drive medulloblastoma recurrence.
abstract: Medulloblastoma (MB), the most common malignant paediatric brain tumor, is currently treated using a combination of surgery, craniospinal radiotherapy and chemotherapy. Owing to MB stem cells (MBSCs), a subset of MB patients remains untreatable despite standard therapy. CD133 is used to identify MBSCs although its functional role in tumorigenesis has yet to be determined. In this work, we showed enrichment of CD133 in Group 3 MB is associated with increased rate of metastasis and poor clinical outcome. The signal transducers and activators of transcription-3 (STAT3) pathway are selectively activated in CD133+MBSCs and promote tumorigenesis through regulation of c-MYC, a key genetic driver of Group 3 MB. We screened compound libraries for STAT3 inhibitors and treatment with the selected STAT3 inhibitors resulted in tumor size reduction in vivo. We propose that inhibition of STAT3 signaling in MBSCs may represent a potential therapeutic strategy to treat patients with recurrent MB.
authors: McMaster Stem Cell and Cancer Research Institute, Hamilton, Ontario, Canada.|Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: N
authors: N
authors: Garg
authors: McMaster Stem Cell and Cancer Research Institute, Hamilton, Ontario, Canada.|Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: D
authors: D
authors: Bakhshinyan
authors: McMaster Stem Cell and Cancer Research Institute, Hamilton, Ontario, Canada.|Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: C
authors: C
authors: Venugopal
authors: McMaster Stem Cell and Cancer Research Institute, Hamilton, Ontario, Canada.|Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: S
authors: S
authors: Mahendram
authors: Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada.
authors: D A
authors: DA
authors: Rosa
authors: McMaster Stem Cell and Cancer Research Institute, Hamilton, Ontario, Canada.|Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.|Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: T
authors: T
authors: Vijayakumar
authors: McMaster Stem Cell and Cancer Research Institute, Hamilton, Ontario, Canada.|Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.|Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors: B
authors: B
authors: Manoranjan
authors: McMaster Centre for Functional Genomics, McMaster University, Hamilton, Ontario, Canada.
authors: R
authors: R
authors: Hallett
authors: McMaster Stem Cell and Cancer Research Institute, Hamilton, Ontario, Canada.|Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: N
authors: N
authors: McFarlane
authors: Departement of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors: K H
authors: KH
authors: Delaney
authors: Departement of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.|Department of Neurosurgery and Paediatric Neurosurgery, Medical University of Lublin, Lublin, Poland.
authors: J M
authors: JM
authors: Kwiecien
authors: Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada.
authors: C C
authors: CC
authors: Arpin
authors: Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada.
authors: P-S
authors: PS
authors: Lai
authors: Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada.
authors: R F
authors: RF
authors: Gómez-Biagi
authors: Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt.
authors: A M
authors: AM
authors: Ali
authors: Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada.
authors: E D
authors: ED
authors: de Araujo
authors: Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: O A
authors: OA
authors: Ajani
authors: McMaster Stem Cell and Cancer Research Institute, Hamilton, Ontario, Canada.|Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.|McMaster Centre for Functional Genomics, McMaster University, Hamilton, Ontario, Canada.|Departments of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors: J A
authors: JA
authors: Hassell
authors: Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada.
authors: P T
authors: PT
authors: Gunning
authors: McMaster Stem Cell and Cancer Research Institute, Hamilton, Ontario, Canada.|Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.|Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.|Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors: S K
authors: SK
authors: Singh
mesh_terms: D000071916:AC133 Antigen / Q000096:biosynthesis* / Q000276:immunology; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D064593:Heterografts; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D000071916:AC133 Antigen; C000606023:PROM1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D054852:Small Molecule Libraries