title: mTOR inhibition decreases SOX2-SOX9 mediated glioma stem cell activity and temozolomide resistance.
abstract: BACKGROUND
  SOX2 and SOX9 are commonly overexpressed in glioblastoma, and regulate the activity of glioma stem cells (GSCs). Their specific and overlapping roles in GSCs and glioma treatment remain unclear.
  
  
  METHODS
  SOX2 and SOX9 levels were examined in human biopsies. Gain and loss of function determined the impact of altering SOX2 and SOX9 on cell proliferation, senescence, stem cell activity, tumorigenesis and chemoresistance.
  
  
  RESULTS
  SOX2 and SOX9 expression correlates positively in glioma cells and glioblastoma biopsies. High levels of SOX2 bypass cellular senescence and promote resistance to temozolomide. Mechanistic investigations revealed that SOX2 acts upstream of SOX9. mTOR genetic and pharmacologic (rapamycin) inhibition decreased SOX2 and SOX9 expression, and reversed chemoresistance.
  
  
  CONCLUSIONS
  Our findings reveal SOX2-SOX9 as an oncogenic axis that regulates stem cell properties and chemoresistance. We identify that rapamycin abrogate SOX protein expression and provide evidence that a combination of rapamycin and temozolomide inhibits tumor growth in cells with high SOX2/SOX9.
authors.affiliation: a Cellular Oncology group , Biodonostia Institute , San Sebastian , Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Garros-Regulez
authors.affiliation: a Cellular Oncology group , Biodonostia Institute , San Sebastian , Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Aldaz
authors.affiliation: a Cellular Oncology group , Biodonostia Institute , San Sebastian , Spain.
authors.forename: Olatz
authors.initials: O
authors.lastname: Arrizabalaga
authors.affiliation: c Stem Cell Biology and Developmental Genetics laboratory , The Francis Crick Institute , London , UK.
authors.forename: Veronica
authors.initials: V
authors.lastname: Moncho-Amor
authors.affiliation: a Cellular Oncology group , Biodonostia Institute , San Sebastian , Spain.
authors.forename: Estefania
authors.initials: E
authors.lastname: Carrasco-Garcia
authors.affiliation: a Cellular Oncology group , Biodonostia Institute , San Sebastian , Spain.
authors.forename: Lorea
authors.initials: L
authors.lastname: Manterola
authors.affiliation: a Cellular Oncology group , Biodonostia Institute , San Sebastian , Spain.
authors.forename: Leire
authors.initials: L
authors.lastname: Moreno-Cugnon
authors.affiliation: b Neuro-Oncology Committee , Donostia Hospital , San Sebastian , Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Barrena
authors.affiliation: a Cellular Oncology group , Biodonostia Institute , San Sebastian , Spain.|b Neuro-Oncology Committee , Donostia Hospital , San Sebastian , Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Villanua
authors.affiliation: a Cellular Oncology group , Biodonostia Institute , San Sebastian , Spain.|b Neuro-Oncology Committee , Donostia Hospital , San Sebastian , Spain.
authors.forename: Irune
authors.initials: I
authors.lastname: Ruiz
authors.affiliation: d Neural Stem Cells and Brain Cancer group , MRC Centre for Regenerative Medicine , Edinburgh , UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Pollard
authors.affiliation: c Stem Cell Biology and Developmental Genetics laboratory , The Francis Crick Institute , London , UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Lovell-Badge
authors.affiliation: a Cellular Oncology group , Biodonostia Institute , San Sebastian , Spain.|b Neuro-Oncology Committee , Donostia Hospital , San Sebastian , Spain.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sampron
authors.affiliation: a Cellular Oncology group , Biodonostia Institute , San Sebastian , Spain.|e IKERBASQUE , Basque Foundation for Science , Bilbao , Spain.
authors.forename: Idoia
authors.initials: I
authors.lastname: Garcia
authors.affiliation: a Cellular Oncology group , Biodonostia Institute , San Sebastian , Spain.|b Neuro-Oncology Committee , Donostia Hospital , San Sebastian , Spain.|e IKERBASQUE , Basque Foundation for Science , Bilbao , Spain.
authors.forename: Ander
authors.initials: A
authors.lastname: Matheu
mesh_terms: D000328:Adult; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: C527782:SOX2 protein, human; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D055748:SOXB1 Transcription Factors; D003606:Dacarbazine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D000077204:Temozolomide
keywords: Glioma stem cell; SOX2; SOX9; rapamycin and temozolomide; senescence