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

doi:10.1038/s41556-019-0407-1

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

Diabetes

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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. CD9^high cells had increased organoid formation capability, and generated tumour grafts in vivo at limiting dilutions. Tumours initiated from CD9^high cells recapitulated the cellular heterogeneity of primary PDAC, whereas CD9^low cells produced only duct-like epithelial progeny. CD9 knockdown decreased the growth of PDAC organoids, and heterozygous CD9 deletion in Pdx1-Cre; LSL-KRas^G12D; p53^F/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 language	English
Pages (from-to)	1425-1435
Number of pages	11
Journal	Nature cell biology
Volume	21
Issue number	11
Early online date	4 Nov 2019
DOIs	https://doi.org/10.1038/s41556-019-0407-1
Publication status	Published - 4 Nov 2019

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CD9 identifies pancreatic cancer stem cells_BEHRENS_Publishedonline4November2019_GREEN AAMAccepted author manuscript, 5.91 MB

https://europepmc.org/article/MED/31685994

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Wang, V. M. Y., Ferreira, R. M. M., Almagro, J., Evan, T., Legrave, N., Zaw Thin, M., Frith, D., Carvalho, J., Barry, D. J., Snijders, A. P., Herbert, E., Nye, E. L., MacRae, J. I., & Behrens, A. (2019). CD9 identifies pancreatic cancer stem cells and modulates glutamine metabolism to fuel tumour growth. Nature cell biology, 21(11), 1425-1435. https://doi.org/10.1038/s41556-019-0407-1

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title = "CD9 identifies pancreatic cancer stem cells and modulates glutamine metabolism to fuel tumour growth",

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.",

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

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AU - Wang, Victoria M.Y.

AU - Ferreira, Rute M.M.

AU - Almagro, Jorge

AU - Evan, Theodore

AU - Legrave, Nathalie

AU - Zaw Thin, May

AU - Frith, David

AU - Carvalho, Joana

AU - Barry, David J.

AU - Snijders, Ambrosius P.

AU - Herbert, Eleanor

AU - Nye, Emma L.

AU - MacRae, James I.

AU - Behrens, Axel

PY - 2019/11/4

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N2 - 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.

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

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