CD9 identifies pancreatic cancer stem cells and modulates glutamine metabolism to fuel tumour growth

Victoria M.Y. Wang, Rute M.M. Ferreira, Jorge Almagro, Theodore Evan, Nathalie Legrave, May Zaw Thin, David Frith, Joana Carvalho, David J. Barry, Ambrosius P. Snijders, Eleanor Herbert, Emma L. Nye, James I. MacRae, Axel Behrens*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

89 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1425-1435
Number of pages11
JournalNature Cell Biology
Volume21
Issue number11
DOIs
Publication statusPublished - 1 Nov 2019
Externally publishedYes

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