Potent EMT and CSC Phenotypes Are Induced By Oncostatin-M in Pancreatic Cancer.
Potent EMT and CSC Phenotypes Are Induced By Oncostatin-M in Pancreatic Cancer.
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DOI：
10.1158/1541-7786.mcr-16-0337
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发表时间：
2017-04
期刊：
影响因子：
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通讯作者：
Jackson MW
中科院分区：
文献类型：
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作者：
Smigiel JM;Parameswaran N;Jackson MW
胰腺导管腺癌（PDAC）由于缺乏明确的症状，缺乏早期检测方法，以及诊断时转移的高频率，被称为沉默杀手。此外，胰腺癌对化疗具有显著的耐药性，临床治疗选择仍然有限。肿瘤微环境（TME）及其相关因素是肿瘤转移能力和耐药的重要决定因素。在这里，抑瘤素M（OSM），IL-6细胞因子家族成员，被确定为间充质和癌症干细胞（CSC）表型的重要驱动因素。此外，在OSM暴露后产生具有间充质/CSC特性的细胞导致增强的致瘤性、增加的转移和对吉西他滨的抗性。OSM诱导ZEB 1、Snail（SNAI 1）和OSM受体（OSMR）的表达，参与正反馈回路以增强间充质/CSC程序。Ruxolitinib对JAK 1/2的抑制阻止了STAT 3介导的ZEB 1、SNAI 1和OSMR的转录，以及间充质/CSC表型的出现。同样，在OSM驱动的间充质/CSC中，通过shRNA介导的敲低，ZEB 1沉默将表型恢复到上皮/非CSC状态。重要的是，具有间充质/CSC特性的细胞的产生是OSM所独有的，并且在IL-6暴露后未观察到，这暗示OSMR和下游效应物信号传导是PDAC中的独特靶标。总体而言，这些数据证明了OSM调节上皮-间充质转化（EMT）/CSC可塑性程序的能力，该程序促进肿瘤发生特性。
Pancreatic ductal adenocarcinoma (PDAC) is referred to as a silent killer due to the lack of clear symptoms, a lack of early detection methods, and a high frequency of metastasis at diagnosis. In addition, pancreatic cancer is remarkably resistant to chemotherapy, and clinical treatment options remain limited. The tumor microenvironment (TME) and associated factors are important determinants of metastatic capacity and drug resistance. Here, oncostatin M (OSM), an IL-6 cytokine family member, was identified as an important driver of mesenchymal and cancer stem cell (CSC) phenotypes. Furthermore, the generation of cells that harbor mesenchymal/CSC properties following OSM exposure resulted in enhanced tumorigenicity, increased metastasis, and resistance to gemcitabine. OSM induced the expression of ZEB1, Snail (SNAI1), and OSM receptor (OSMR), engaging a positive feedback loop to potentiate the mesenchymal/CSC program. Suppression of JAK1/2 by Ruxolitinib prevented STAT3-mediated transcription of ZEB1, SNAI1, and OSMR, as well as the emergence of a mesenchymal/CSC phenotype. Likewise, ZEB1 silencing, by shRNA-mediated knockdown, in OSM-driven mesenchymal/CSC reverted the phenotype back to an epithelial/non-CSC state. Importantly, the generation of cells with mesenchymal/CSC properties was unique to OSM, and not observed following IL-6 exposure, implicating OSMR and downstream effector signaling as a distinct target in PDAC. Overall, these data demonstrate the capacity of OSM to regulate an epithelial-mesenchymal transition (EMT)/CSC plasticity program that promotes tumorigenic properties.