Transforming growth factor β-induced epithelial-to-mesenchymal signature predicts metastasis-free survival in non-small cell lung cancer

// Edna Gordian 1, * , Eric A. Welsh 2, * , Nicholas Gimbrone 3 , Erin M. Siegel 4 , David Shibata 5 , Ben C. Creelan 6 , William Douglas Cress 3 , Steven A. Eschrich 7 , Eric B. Haura 6 and Teresita Muñoz-Antonia 1 1 Tumor Biology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 2 Cancer Informatics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 3 Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 4 Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 5 Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA 6 Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 7 Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA * These authors contributed equally to this work Correspondence to: Teresita Muñoz-Antonia, email: Teresita.Antonia@moffitt.org Keywords: non-small cell lung cancer; epithelial-to-mesenchymal transition; EMT; metastasis; colon cancer Received: December 13, 2017      Accepted: December 29, 2018      Published: January 25, 2019 ABSTRACT Transforming growth factor beta (TGFβ) plays a key role in regulating epithelial-to-mesenchymal transition (EMT). A gene expression signature ( TGFβ-EMT ) associated with TGFβ-induced EMT activities was developed using human Non-Small Cell Lung Carcinoma (NSCLC) cells treated with TGFβ-1 and subjected to Affymetrix microarray analysis. The final 105-probeset TGFβ-EMT signature covers 77 genes, and a NanoString assay utilized a subset of 60 of these genes (TGFβ-EMTN signature). We found that the TGFβ-EMT and TGFβ-EMT N gene signatures predicted overall survival (OS) and metastasis-free survival (MFS). The TGFβ-EMT signature was validated as prognostic of 5-year MFS in 3 cohorts: a 133 NSCLC tumor dataset ( P = 0.0002), a NanoString assays of RNA isolated from formalin-fixed paraffin-embedded samples from these same tumors ( P = 0.0015), and a previously published NSCLC MFS dataset ( P = 0.0015). The separation between high and low metastasis signature scores was higher at 3 years (ΔMFS TGFβ-EMT = -28.6%; ΔMFS TGFβ-EMT N = −25.2%) than at 5 years (ΔMFS TGFβ-EMT = -18.6%; ΔMFS TGFβ-EMT N = −11.8%). In addition, the TGFβ-EMT signature correlated with whether the cancer had already metastasized or not at time of surgery in a colon cancer cohort. The results show that the TGFβ-EMT signature successfully discriminated lung cancer cell lines capable of undergoing EMT in response to TGFβ-1 and predicts MFS in lung adenocarcinomas. Thus, the TGFβ-EMT signature has the potential to be developed as a clinically relevant predictive biomarker, for example to identify those patients with resected early stage lung cancer who may benefit from adjuvant therapy.