title: FoxG1 interacts with Bmi1 to regulate self-renewal and tumorigenicity of medulloblastoma stem cells.
abstract: Brain tumors represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant tumor. Recent studies have demonstrated the presence of several MB molecular subgroups, each distinct in terms of prognosis and predicted therapeutic response. Groups 1 and 2 are characterized by relatively good clinical outcomes and activation of the Wnt and Shh pathways, respectively. In contrast, groups 3 and 4 ("non-Shh/Wnt MBs") are distinguished by metastatic disease, poor patient outcome, and lack a molecular pathway phenotype. Current gene expression platforms have not detected brain tumor-initiating cell (BTIC) self-renewal genes in groups 3 and 4 MBs as BTICs typically comprise a minority of tumor cells and may therefore go undetected on bulk tumor analyses. Since increasing BTIC frequency has been associated with increasing tumor aggressiveness and poor patient outcome, we investigated the subgroup-specific gene expression profile of candidate stem cell genes within 251 primary human MBs from four nonoverlapping MB transcriptional databases (Amsterdam, Memphis, Toronto, Boston) and 74 NanoString-subgrouped MBs (Vancouver). We assessed the functional relevance of two genes, FoxG1 and Bmi1, which were significantly enriched in non-Shh/Wnt MBs and showed these genes to mediate MB stem cell self-renewal and tumor initiation in mice. We also identified their transcriptional regulation through reciprocal promoter occupancy in CD15+ MB stem cells. Our work demonstrates the application of stem cell data gathered from genomic platforms to guide functional BTIC assays, which may then be used to develop novel BTIC self-renewal mechanisms amenable to therapeutic targeting.
authors.affiliation: McMaster University, Hamilton, Ontario, Canada.
authors.forename: Branavan
authors.initials: B
authors.lastname: Manoranjan
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hallett
authors.forename: Chitra
authors.initials: C
authors.lastname: Venugopal
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Mack
authors.forename: Nicole
authors.initials: N
authors.lastname: McFarlane
authors.forename: Sara M
authors.initials: SM
authors.lastname: Nolte
authors.forename: Katrin
authors.initials: K
authors.lastname: Scheinemann
authors.forename: Thorsteinn
authors.initials: T
authors.lastname: Gunnarsson
authors.forename: John A
authors.initials: JA
authors.lastname: Hassell
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Cathy
authors.initials: C
authors.lastname: Lee
authors.forename: Joanna
authors.initials: J
authors.lastname: Triscott
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Foster
authors.forename: Christopher
authors.initials: C
authors.lastname: Dunham
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Dunn
authors.forename: Sheila K
authors.initials: SK
authors.lastname: Singh
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: C069077:BMI1 protein, human; C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D063150:Polycomb Repressive Complex 1
keywords: Bmi1; Brain tumor-initiating cell; FoxG1; Medulloblastoma; Self-renewal; Stem cells