Transforming growth factor β-induced epithelial-to-mesenchymal signature predicts metastasis-free survival in non-small cell lung cancer
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Edna Gordian1,*, Eric A. Welsh2,*, Nicholas Gimbrone3, Erin M. Siegel4, David Shibata5, Ben C. Creelan6, William Douglas Cress3, Steven A. Eschrich7, Eric B. Haura6 and Teresita Muñoz-Antonia1
1Tumor Biology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
2Cancer Informatics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
3Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
4Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
5Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
6Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
7Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
*These authors contributed equally to this work
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
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-EMTN 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-EMTN = −25.2%) than at 5 years (ΔMFS TGFβ-EMT = -18.6%; ΔMFS TGFβ-EMTN = −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.
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