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CD9 identifies pancreatic cancer stem cells and modulates glutamine metabolism to fuel tumour growth.
Wang, Victoria M-Y; Ferreira, Rute M M; Almagro, Jorge; Evan, Theodore; Legrave, Nathalie; Zaw Thin, May; Frith, David; Carvalho, Joana; Barry, David J; Snijders, Ambrosius P; Herbert, Eleanor; Nye, Emma L; MacRae, James I; Behrens, Axel.
Afiliación
  • Wang VM; Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK.
  • Ferreira RMM; Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK.
  • Almagro J; Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, London, UK.
  • Evan T; Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK.
  • Legrave N; Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK.
  • Zaw Thin M; Metabolomics Laboratory, The Francis Crick Institute, London, UK.
  • Frith D; Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK.
  • Carvalho J; Protein Analysis and Proteomics Laboratory, The Francis Crick Institute, London, UK.
  • Barry DJ; Experimental Histopathology Laboratory, The Francis Crick Institute, London, UK.
  • Snijders AP; Advanced Light Microscopy Facility, The Francis Crick Institute, London, UK.
  • Herbert E; Protein Analysis and Proteomics Laboratory, The Francis Crick Institute, London, UK.
  • Nye EL; Department of Pathobiology & Population Sciences, Royal Veterinary College, Hatfield, UK.
  • MacRae JI; Experimental Histopathology Laboratory, The Francis Crick Institute, London, UK.
  • Behrens A; Metabolomics Laboratory, The Francis Crick Institute, London, UK.
Nat Cell Biol ; 21(11): 1425-1435, 2019 11.
Article en En | MEDLINE | ID: mdl-31685994
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) shows great cellular heterogeneity, with pronounced epithelial and mesenchymal cancer cell populations. However, the cellular hierarchy underlying PDAC cell diversity is unknown. Here we identify the tetraspanin CD9 as a marker of PDAC tumour-initiating cells. CD9high cells had increased organoid formation capability, and generated tumour grafts in vivo at limiting dilutions. Tumours initiated from CD9high cells recapitulated the cellular heterogeneity of primary PDAC, whereas CD9low cells produced only duct-like epithelial progeny. CD9 knockdown decreased the growth of PDAC organoids, and heterozygous CD9 deletion in Pdx1-Cre; LSL-KRasG12D; p53F/F mice prolonged overall survival. Mechanistically, CD9 promoted the plasma membrane localization of the glutamine transporter ASCT2, enhancing glutamine uptake in PDAC cells. Thus, our study identifies a PDAC subpopulation capable of initiating PDAC and giving rise to PDAC heterogeneity, suggesting that the cellular diversity of PDAC is generated by PDAC stem cell differentiation.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Células Madre Neoplásicas / Regulación Neoplásica de la Expresión Génica / Antígenos de Histocompatibilidad Menor / Carcinoma Ductal Pancreático / Sistema de Transporte de Aminoácidos ASC / Tetraspanina 29 / Glutamina Idioma: En Revista: Nat Cell Biol Año: 2019 Tipo del documento: Article
Texto completo
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Células Madre Neoplásicas / Regulación Neoplásica de la Expresión Génica / Antígenos de Histocompatibilidad Menor / Carcinoma Ductal Pancreático / Sistema de Transporte de Aminoácidos ASC / Tetraspanina 29 / Glutamina Idioma: En Revista: Nat Cell Biol Año: 2019 Tipo del documento: Article