Abstract
BackgroundEpithelial-to-mesenchymal transition (EMT) enhances motility, stemness, chemoresistance and metastasis. Little is known about how various pathways coordinate to elicit EMT’s different functional aspects in non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) has been previously correlated with EMT transcription factor ZEB1 in NSCLC and imparts resistance against anti-folate chemotherapy. In this study, we establish a functional correlation between TS, EMT, chemotherapy and metastasis and propose a network for TS mediated EMT.MethodsPublished datasets were analysed to evaluate the significance of TS in NSCLC fitness and prognosis. Promoter reporter assay was used to sort NSCLC cell lines in TSHIGH and TSLOW. Metastasis was assayed in a syngeneic mouse model.ResultsTS levels were prognostic and predicted chemotherapy response. Cell lines with higher TS promoter activity were more mesenchymal-like. RNA-seq identified EMT as one of the most differentially regulated pathways in connection to TS expression. EMT transcription factors HOXC6 and HMGA2 were identified as upstream regulator of TS, and AXL, SPARC and FOSL1 as downstream effectors. TS knock-down reduced the metastatic colonisation in vivo.ConclusionThese results establish TS as a theranostic NSCLC marker integrating survival, chemo-resistance and EMT, and identifies a regulatory network that could be targeted in EMT-driven NSCLC.
Highlights
Epithelial-to-mesenchymal transition (EMT) enhances motility, stemness, chemoresistance and metastasis
As a rate-limiting de novo pyrimidine biosynthesis enzyme, TYMS has been proposed as an essential gene, but so far, no functional data have been shown in non-small cell lung cancer (NSCLC)
To evaluate dependency of NSCLC on Thymidylate synthase (TS), a dataset generated from a genome-wide CRISPR/Cas[9] screen of 18,009 genes in 324 cancer cell lines was exploited.[14]
Summary
Epithelial-to-mesenchymal transition (EMT) enhances motility, stemness, chemoresistance and metastasis. EMT-TFs activate multiple molecular pathways that leads to alteration in cytoskeleton and cell-adhesion proteins.[3] EMT is a key early event in NSCLC biology and steers epithelial-like cells towards stemness, chemoresistance and metastatic dissemination.[4,5]. It is engineered through coordination of divergent molecular pathways,[6] and presumably orchestrated by different EMT-TFs at different progression time points.[7,8,9] How these pathways connect to each other and affect different modalities of EMT is still largely unexplored
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
