Thymidylate synthase drives the phenotypes of epithelial-to-mesenchymal transition in non-small cell lung cancer

Epithelial to mesenchymal transition (EMT) is a developmental process driving metastasis and chemoresistance. Thymidylate synthase (TS) is a proliferation enzyme and a chemotherapeutic drug target we previously correlated with EMT. Here we report a rather direct role of TS in determining EMT phenotypes in non-small cell lung cancer (NSCLC). TS knockdown and a promoter reporter system revealed the control of TS on EMT, and upstream regulators (HMGA2, HOXC6) and downstream effectors (AXL, SPARC, FOSL1) were identified. In vivo, TS knockdown suppressed lung colonization and metastasis formation in a proliferation-independent manner. Transcriptomic analyses showed a significant enrichment of EMT signature genes in NSCLC patients with high TS levels. These results establish the role of TS as a theranostic NSCLC marker mediating survival, chemo-resistance and EMT, and identifies a regulatory network that could be exploited to target EMT-driven NSCLC. Gene epxression analysis by RNAseq in Lung Adenocarcinma Cell Lines A549 and Calu1 with knock down of Thymidylate Synthase and scrambled pLKO control.