title: Purine synthesis promotes maintenance of brain tumor initiating cells in glioma.
abstract: Brain tumor initiating cells (BTICs), also known as cancer stem cells, hijack high-affinity glucose uptake active normally in neurons to maintain energy demands. Here we link metabolic dysregulation in human BTICs to a nexus between MYC and de novo purine synthesis, mediating glucose-sustained anabolic metabolism. Inhibiting purine synthesis abrogated BTIC growth, self-renewal and in vivo tumor formation by depleting intracellular pools of purine nucleotides, supporting purine synthesis as a potential therapeutic point of fragility. In contrast, differentiated glioma cells were unaffected by the targeting of purine biosynthetic enzymes, suggesting selective dependence of BTICs. MYC coordinated the control of purine synthetic enzymes, supporting its role in metabolic reprogramming. Elevated expression of purine synthetic enzymes correlated with poor prognosis in glioblastoma patients. Collectively, our results suggest that stem-like glioma cells reprogram their metabolism to self-renew and fuel the tumor hierarchy, revealing potential BTIC cancer dependencies amenable to targeted therapy.
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Xiuxing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Kailin
authors.identifier: http://orcid.org/0000-0001-5968-6738
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Qiulian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Mack
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.|Institute of Pathology and Southwest Cancer Center, Southwest Hospital, The Third Military Medical University, and The Key Laboratory of Tumor Immunopathology, The Ministry of Education of China, Chongqing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Leo J Y
authors.initials: LJY
authors.lastname: Kim
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Briana C
authors.initials: BC
authors.lastname: Prager
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Flavahan
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Meromit
authors.initials: M
authors.lastname: Singer
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Hubert
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Tyler E
authors.initials: TE
authors.lastname: Miller
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Fang
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Mario L
authors.identifier: http://orcid.org/0000-0001-9898-5351
authors.initials: ML
authors.lastname: Suvà
authors.affiliation: Department of Quantitative Health Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Hwang
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Jason W
authors.identifier: http://orcid.org/0000-0002-7766-3502
authors.initials: JW
authors.lastname: Locasale
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Shideng
authors.initials: S
authors.lastname: Bao
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
mesh_terms: D000249:Adenosine Monophosphate / Q000096:biosynthesis; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D023281:Genomics; D005910:Glioma / Q000201:enzymology / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D006157:Guanosine Monophosphate / Q000096:biosynthesis; D006801:Humans; D055432:Metabolomics; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011687:Purines / Q000096:biosynthesis*; D012268:Ribose-Phosphate Pyrophosphokinase / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011687:Purines; D000249:Adenosine Monophosphate; D006157:Guanosine Monophosphate; C510474:PRPS1 protein, human; D012268:Ribose-Phosphate Pyrophosphokinase; C030985:purine