CD9 identifies pancreatic cancer stem cells and modulates glutamine metabolism to fuel tumour growth
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Victoria Wang Rute Ferreira Jorge Almagro Theo Evan Nathalie Legrave May Zaw Thin David Frith Joana Do Vale Viegas Silva Carvalho David Barry Bram Snijders Eleanor Herbert Emma Nye James Macrae Axel BehrensAbstract
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.
Journal details
Journal Nature Cell Biology
Volume 21
Issue number 11
Pages 1425-1435
Available online
Publication date
Full text links
Publisher website (DOI) 10.1038/s41556-019-0407-1
Figshare View on figshare
Europe PubMed Central 31685994
Pubmed 31685994
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Related topics
- Tumour Biology
- Stem Cells
- Signalling & Oncogenes
- Model Organisms
- Metabolism
- Infectious Disease
- Immunology
- Imaging
- Human Biology & Physiology
- Genome Integrity & Repair
- Genetics & Genomics
- Gene Expression
- Developmental Biology
- Computational & Systems Biology
- Chemical Biology & High Throughput
- Cell Biology
- Biochemistry & Proteomics
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