title: Pten and p53 converge on c-Myc to control differentiation, self-renewal, and transformation of normal and neoplastic stem cells in glioblastoma.
abstract: Glioblastoma (GBM) is a highly lethal primary brain cancer with hallmark features of diffuse invasion, intense apoptosis resistance and florid necrosis, robust angiogenesis, and an immature profile with developmental plasticity. In the course of assessing the developmental consequences of central nervous system (CNS)-specific deletion of p53 and Pten, we observed a penetrant acute-onset malignant glioma phenotype with striking clinical, pathological, and molecular resemblance to primary GBM in humans. This primary, as opposed to secondary, GBM presentation in the mouse prompted genetic analysis of human primary GBM samples that revealed combined p53 and Pten mutations as the most common tumor suppressor defects in primary GBM. On the mechanistic level, the "multiforme" histopathological presentation and immature differentiation marker profile of the murine tumors motivated transcriptomic promoter-binding element and functional studies of neural stem cells (NSCs), which revealed that dual, but not singular, inactivation of p53 and Pten promotes cellular c-Myc activation. This increased c-Myc activity is associated not only with impaired differentiation, enhanced self-renewal capacity of NSCs, and tumor-initiating cells (TICs), but also with maintenance of TIC tumorigenic potential. Together, these murine studies have provided a highly faithful model of primary GBM, revealed a common tumor suppressor mutational pattern in human disease, and established c-Myc as a key component of p53 and Pten cooperative actions in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal, and tumorigenic potential.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard MedicalSchool, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zheng
authors.forename: H
authors.initials: H
authors.lastname: Ying
authors.forename: H
authors.initials: H
authors.lastname: Yan
authors.forename: A C
authors.initials: AC
authors.lastname: Kimmelman
authors.forename: D J
authors.initials: DJ
authors.lastname: Hiller
authors.forename: A-J
authors.initials: AJ
authors.lastname: Chen
authors.forename: S R
authors.initials: SR
authors.lastname: Perry
authors.forename: G
authors.initials: G
authors.lastname: Tonon
authors.forename: G C
authors.initials: GC
authors.lastname: Chu
authors.forename: Z
authors.initials: Z
authors.lastname: Ding
authors.forename: J M
authors.initials: JM
authors.lastname: Stommel
authors.forename: K L
authors.initials: KL
authors.lastname: Dunn
authors.forename: R
authors.initials: R
authors.lastname: Wiedemeyer
authors.forename: M J
authors.initials: MJ
authors.lastname: You
authors.forename: C
authors.initials: C
authors.lastname: Brennan
authors.forename: Y A
authors.initials: YA
authors.lastname: Wang
authors.forename: K L
authors.initials: KL
authors.lastname: Ligon
authors.forename: W H
authors.initials: WH
authors.lastname: Wong
authors.forename: L
authors.initials: L
authors.lastname: Chin
authors.forename: R A
authors.initials: RA
authors.lastname: dePinho
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D016259:Genes, myc; D016158:Genes, p53; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008959:Models, Neurological; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D013045:Species Specificity
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse