Thymidylate synthase prompts metastatic progression through the dTMP associated EMT process in pancreatic ductal adenocarcinoma

• Published in: Cancer letters 2018-04, Vol.419, p.40-52
• Main Authors: Kang, Muxing, Zheng, Wen, Chen, Qing, Qin, Wenjie, Li, Pengping, Huang, Shifei, Zhou, Yizhao, Wang, Lantian, Cai, Haolei, Lu, Wenjie, Jiang, Biao, Guo, Qingqu, Chen, Jian, Wan, Dylan, Rao, Jianyu, Wu, Yulian
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Animal models; Biosynthesis; Cancer; Causation; Cell division; Cell growth; Cytoplasm; Deoxyribonucleotide triphosphate nucleoside pools balance; Epithelial to mesenchymal transition; Gene expression; Lesions; Medical prognosis; Mesenchyme; Metastases; Metastasis; Pancreas; Pancreatic cancer; Pancreatic ductal adenocarcinoma; Ribonucleotide reductase; Standardization; Thymidylate synthase
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2018.01.026

As a fundamental metabolic enzyme, anti-Thymidylate synthase (TS) strategy has been shown to be an effective therapy for human cancers. However, the genuine effects of TS in pancreatic ductal adenocarcinoma (PDA) are still conflicting. We systemically assessed the prognostic value and whether TS associated with malignant progression in PDA. Protein and mRNA expression level of TS were evaluated in en bloc PDA samples, the prognostic effect of TS expressed in cytoplasm or cytonuclear was determined separately in the first time. The impact of TS on tumor cell behaviors was assessed in in vitro assays, and the TS associated metastatic potential was further determined in two different PDA metastatic models. The retrospective clinical analysis firstly demonstrated that tumor cytonuclear TS expression was positively correlated with lymphatic metastasis and negatively correlated with the overall survival (OS) in PDA patients. The subsequent experiments further confirmed that TS depletion can effectively abate EMT (epithelial to mesenchymal) process in in vitro and decline most of the metastatic lesions in two different PDA mice models, and the deoxythymidine monophosphate (dTMP) biosynthesis malfunction resulted imbalanced dNTP pools may be the fundamental causation. Collectively, the present study suggested the prospective strategy of combined anti-TS scheme for metastatic PDA, and we strongly suggest further clinical standardization research with a large cohort to verify the prognostic value and the therapeutic potential of TS in PDA. •Experimental evidences for the application of anti-TS strategy in metastatic PDA.•Tumor nucleus TS expression suggests lymphatic metastasis and poor prognosis in PDA.•TS is intimately related with metastatic phenotype in two mouse models of PDA.•dNTP pools imbalance may be deeply involved in the TS associated metastasis in PDA.