Targeting Notch and EGFR signaling in human mucoepidermoid carcinoma.
Targeting Notch and EGFR signaling in human mucoepidermoid carcinoma.
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DOI：
10.1038/s41392-020-00388-0
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发表时间：
2021-01-21
影响因子：
39.3
通讯作者：
Wu L
中科院分区：
文献类型：
--
作者：
Ni W;Chen Z;Zhou X;Yang R;Yu M;Lu J;Kaye FJ;Wu L
粘液表皮样癌（MEC）是最常见的唾液腺癌类型，晚期、转移性和复发性MEC患者的治疗选择有限，治疗结局较差。MEC通常与编码CRTC 1-MAML 2致癌融合的染色体易位t（11;19）（q14-21;p12-13）相关。CRTC 1-MAML 2融合是MEC生长所需的，部分是通过诱导自分泌AREG-EGFR信号传导。越来越多的证据表明，MEC恶性肿瘤由癌症干细胞样细胞维持。在这项研究中，我们的目的是确定维持MEC干细胞样细胞的关键信号传导，以及干细胞信号传导和CRTC 1-MAML 2诱导的EGFR信号传导的联合靶向对阻断MEC生长的影响。首先，我们评估了Notch信号在调节MEC干细胞样细胞中的意义。在人融合阳性MEC细胞中检测到异常激活的Notch信号传导。用遗传或药理学抑制剂抑制Notch信号传导在体外减少六钩蚴形成和ALDH-bright群体，并在体内阻断MEC异种移植物的生长。接下来，我们研究了共靶向Notch信号传导和EGFR信号传导的作用，并观察到对体内MEC生长的增强抑制。总的来说，这项研究确定了Notch信号传导在维持MEC干细胞样细胞和肿瘤生长中的关键作用，并揭示了一种共同靶向Notch和EGFR信号传导作为潜在有效的抗MEC治疗的新方法。
Mucoepidermoid carcinoma (MEC) is the most common type of salivary gland cancers and patients with advanced, metastatic, and recurrent MECs have limited therapeutic options and poor treatment outcomes. MEC is commonly associated with a chromosomal translocation t(11;19) (q14-21;p12-13) that encodes the CRTC1-MAML2 oncogenic fusion. The CRTC1-MAML2 fusion is required for MEC growth in part through inducing autocrine AREG-EGFR signaling. Growing evidence suggests that MEC malignancy is maintained by cancer stem-like cells. In this study, we aimed to determine critical signaling for maintaining MEC stem-like cells and the effect of combined targeting of stem cell signaling and CRTC1-MAML2-induced EGFR signaling on blocking MEC growth. First, we evaluated the significance of Notch signaling in regulating MEC stem-like cells. Aberrantly activated Notch signaling was detected in human fusion-positive MEC cells. The inhibition of Notch signaling with genetic or pharmacological inhibitors reduced oncosphere formation and ALDH-bright population in vitro and blocked the growth of MEC xenografts in vivo. Next, we investigated the effect of co-targeting Notch signaling and EGFR signaling, and observed enhanced inhibition on MEC growth in vivo. Collectively, this study identified a critical role of Notch signaling in maintaining MEC stem-like cells and tumor growth, and revealed a novel approach of co-targeting Notch and EGFR signaling as a potential effective anti-MEC treatment.
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影响因子：
8
作者：
Chen, Z.;Chen, J.;Wu, L.
通讯作者：
Wu, L.
DOI：
10.1073/pnas.1319176111
发表时间：
2014-08-12
影响因子：
11.1
作者：
Amelio, Antonio L.;Fallahi, Mohammad;Conkright, Michael D.
通讯作者：
Conkright, Michael D.
EGFR阻断通过Notch3依赖性信号传导富集了肺癌干细胞。
影响因子：
11.2
作者：
Arasada RR;Amann JM;Rahman MA;Huppert SS;Carbone DP
通讯作者：
Carbone DP
影响因子：
--
作者：
Adams A;Warner K;Pearson AT;Zhang Z;Kim HS;Mochizuki D;Basura G;Helman J;Mantesso A;Castilho RM;Wicha MS;Nör JE
通讯作者：
Nör JE
影响因子：
11.2
作者：
Coxon, A;Rozenblum, E;Kaye, FJ
通讯作者：
Kaye, FJ