CD9 identifies pancreatic cancer stem cells and modulates glutamine metabolism to fuel tumour growth.,Nature Cell Biology

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CD9 identifies pancreatic cancer stem cells and modulates glutamine metabolism to fuel tumour growth.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2019-11-04 , DOI: 10.1038/s41556-019-0407-1
Victoria M-Y Wang ₁ , Rute M M Ferreira _{1,

2} , Jorge Almagro ₁ , Theodore Evan ₁ , Nathalie Legrave ₃ , May Zaw Thin ₁ , David Frith ₄ , Joana Carvalho ₅ , David J Barry ₆ , Ambrosius P Snijders ₄ , Eleanor Herbert ₇ , Emma L Nye ₅ , James I MacRae ₃ , Axel Behrens _{1,

8}

Affiliation

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.

中文翻译：

CD9 识别胰腺癌干细胞并调节谷氨酰胺代谢以促进肿瘤生长。

胰腺导管腺癌 (PDAC) 显示出巨大的细胞异质性，具有明显的上皮和间充质癌细胞群。然而，PDAC 细胞多样性背后的细胞层次结构是未知的。在这里，我们将四跨膜蛋白 CD9 鉴定为 PDAC 肿瘤起始细胞的标志物。CD9high 细胞具有增加的类器官形成能力，并在有限稀释度下在体内产生肿瘤移植物。从 CD9high 细胞起始的肿瘤概括了原代 PDAC 的细胞异质性，而 CD9low 细胞仅产生导管样上皮后代。CD9 敲低降低了 PDAC 类器官的生长，以及 Pdx1-Cre 中的杂合 CD9 缺失；LSL-KRasG12D；p53F/F 小鼠延长了总生存期。从机制上讲，CD9 促进了谷氨酰胺转运蛋白 ASCT2 的质膜定位，增强 PDAC 细胞中谷氨酰胺的摄取。因此，我们的研究确定了一个能够启动 PDAC 并引起 PDAC 异质性的 PDAC 亚群，这表明 PDAC 的细胞多样性是由 PDAC 干细胞分化产生的。

更新日期：2019-11-04

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