Cancer-initiating cells in human pancreatic cancer organoids are maintained by interactions with endothelial cells
Cancer-initiating cells in human pancreatic cancer organoids are maintained by interactions with endothelial cells
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DOI：
10.1016/j.canlet.2020.10.012
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发表时间：
2021-02-01
期刊：
影响因子：
9.7
通讯作者：
Lim, Jong-Baeck
中科院分区：
文献类型：
--
作者：
Choi, Jae-Il;Jang, Sung Ill;Lim, Jong-Baeck
胰腺导管腺癌（PDAC）由于存在癌症起始细胞（CIC）和肿瘤微环境（TME）的特征而显示出预后差和高度恶性。类器官对于研究PDAC是有用的，并且建立类器官依赖于干细胞生长因子，包括Wnt信号传导。在本文中，使用常规的类器官培养系统，我们证明了CD 44（+）CD 24（+）和CD 44（+）CD 24（+）EpCAM（+）CIC在PDAC患者来源的类器官中富集>65%。表达CD 44的CIC通过聚集成圈形成管腔结构。此外，类器官来源的CD 44（-）癌细胞能够类器官重新形成，并且可以在类器官培养系统中重新编程为表达CD 44的CIC。为了模拟不存在人工干细胞生长因子的TME，建立了具有血管龛的PDAC类器官。PDAC肿瘤类器官中的CIC通过旁分泌效应和与内皮细胞的直接相互作用来维持。有趣的是，PDAC肿瘤组织中的CD 44（+）细胞主要在血管龛中检测到。抑制内皮细胞中的Wnt和Notch信号传导可抑制类器官形成和CD 24（+）CD 44（+）CIC的维持。总的来说，我们的结果表明，PDAC患者源性类器官通过Wnt和Notch途径与内皮细胞相互作用来维持CIC。
Pancreatic ductal adenocarcinoma (PDAC) shows poor prognosis and high malignancy due to the presence of cancer-initiating cells (CICs) and characteristics of the tumor microenvironment (TME). Organoids are useful for studying PDAC, and establishing organoids is dependent on stem cell growth factors, including Wnt signaling. Herein, using a conventional organoid culture system, we demonstrated that CD44(+)CD24(+) and CD44(+) CD24(+)EpCAM(+) CICs were enriched >65% in a PDAC patient-derived organoid. CICs expressing CD44 formed lumen structures by gathering into circles. Additionally, organoid-derived CD44(-) cancer cells were capable of organoid re-formation and could be re-programed as CD44-expressing CICs in the organoid culture system. To mimic a TME absent artificial stem cell growth factors, a PDAC organoid with vascular niche was established. CICs in the PDAC tumor organoid were maintained by paracrine effects and direct interactions with endothelial cells. Interestingly, CD44(+) cells in PDAC tumor tissue were detected primarily in the vascular niche. Inhibiting both Wnt and Notch signaling in endothelial cells suppressed organoid formation and the maintenance of CD24(+)CD44(+) CICs. Collectively, our results suggest that PDAC patient-derived organoids maintain CICs by interacting with endothelial cells via Wnt and Notch pathways.