期刊
MOLECULAR CANCER RESEARCH
卷 15, 期 4, 页码 478-488出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-16-0337
关键词
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资金
- Case Comprehensive Cancer Center [P30 CA43703]
- NIH [R01CA138421]
- American Cancer Society [RSG CCG-122517]
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, oncostatinM(OSM), an IL6 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 IL6 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. Implications: Therapeutic targeting the OSM/OSMR axis within the TME may prevent or reverse the aggressive mesenchymal and CSC phenotypes associated with poor outcomes in patients with PDAC. (C) 2017 AACR.
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