title: Glutathione biosynthesis is upregulated at the initiation of MYCN-driven neuroblastoma tumorigenesis.
abstract: The MYCN gene is amplified and overexpressed in a large proportion of high stage neuroblastoma patients and has been identified as a key driver of tumorigenesis. However, the mechanism by which MYCN promotes tumor initiation is poorly understood. Here we conducted metabolic profiling of pre-malignant sympathetic ganglia and tumors derived from the TH-MYCN mouse model of neuroblastoma, compared to non-malignant ganglia from wildtype littermates. We found that metabolites involved in the biosynthesis of glutathione, the most abundant cellular antioxidant, were the most significantly upregulated metabolic pathway at tumor initiation, and progressively increased to meet the demands of tumorigenesis. A corresponding increase in the expression of genes involved in ribosomal biogenesis suggested that MYCN-driven transactivation of the protein biosynthetic machinery generated the necessary substrates to drive glutathione biosynthesis. Pre-malignant sympathetic ganglia from TH-MYCN mice had higher antioxidant capacity and required glutathione upregulation for cell survival, when compared to wildtype ganglia. Moreover, in vivo administration of inhibitors of glutathione biosynthesis significantly delayed tumorigenesis when administered prophylactically and potentiated the anticancer activity of cytotoxic chemotherapy against established tumors. Together these results identify enhanced glutathione biosynthesis as a selective metabolic adaptation required for initiation of MYCN-driven neuroblastoma, and suggest that glutathione-targeted agents may be used as a potential preventative strategy, or as an adjuvant to existing chemotherapies in established disease.
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia; School of Women's & Children's Health, UNSW Australia, Randwick, New South Wales 2031, Australia.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Carter
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia.
authors.forename: Selina K
authors.initials: SK
authors.lastname: Sutton
authors.affiliation: The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2010, Australia.
authors.forename: Marina
authors.initials: M
authors.lastname: Pajic
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia.
authors.forename: Jayne
authors.initials: J
authors.lastname: Murray
authors.affiliation: Endeavour College of Natural Health, Sydney, 2000, Australia.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Sekyere
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia.
authors.forename: Jamie
authors.initials: J
authors.lastname: Fletcher
authors.affiliation: Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Beckers
authors.affiliation: Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Katleen
authors.initials: K
authors.lastname: De Preter
authors.affiliation: Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Department of Pediatric Hematology and Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Rani E
authors.initials: RE
authors.lastname: George
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia; University of New South Wales, Centre for Childhood Cancer Research, Randwick, New South Wales 2031, Australia.
authors.forename: Murray D
authors.initials: MD
authors.lastname: Norris
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia; School of Women's & Children's Health, UNSW Australia, Randwick, New South Wales 2031, Australia. Electronic address: BCheung@ccia.unsw.edu.au.
authors.forename: Belamy B
authors.initials: BB
authors.lastname: Cheung
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia; Kids Cancer Centre, Sydney Children's Hospital, Randwick 2031, Australia. Electronic address: g.marshall@unsw.edu.au.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
mesh_terms: D000818:Animals; D053898:Biosynthetic Pathways; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005728:Ganglia, Sympathetic / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D055442:Metabolome; D051379:Mice; D008822:Mice, Transgenic; D000071447:N-Myc Proto-Oncogene Protein / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D010524:Peripheral Nervous System Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D005978:Glutathione
keywords: BSO; Glutathione; MYCN; Metabolomics; Neuroblastoma; Tumorigenesis