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

ABSTRACT

Transforming growth factor beta (TGFß) plays a key role in regulating epithelial-to-mesenchymal transition (EMT). A gene expression signature (TGFß-EMT) associated with TGFß-induced EMT activities was developed using human Non-Small Cell Lung Carcinoma (NSCLC) cells treated with TGFß-1 and subjected to Affymetrix microarray analysis. The final 105-probeset TGFß-EMT signature covers 77 genes, and a NanoString assay utilized a subset of 60 of these genes (TGFß-EMTN signature). We found that the TGFß-EMT and TGFß-EMTN gene signatures predicted overall survival (OS) and metastasis-free survival (MFS). The TGFß-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 TGFß-EMT = -28.6%; ΔMFS TGFß-EMTN = -25.2%) than at 5 years (ΔMFS TGFß-EMT = -18.6%; ΔMFS TGFß-EMTN = -11.8%). In addition, the TGFß-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 TGFß-EMT signature successfully discriminated lung cancer cell lines capable of undergoing EMT in response to TGFß-1 and predicts MFS in lung adenocarcinomas. Thus, the TGFß-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.