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

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-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.

Uronic acid pathway metabolites regulate mesenchymal transition and invasiveness in lung adenocarcinoma

“…Wang et al provide evidence that enhanced expression of pELAV1/Hur and SNAI1 cellular markers of mesenchymal transition are associated with reduced survival in patients with conventional treatment. These findings are consistent with earlier studies that have identified more classical markers of mesenchymal transition as markers for reduced survival (22) and resistance to EGFR inhibitor therapy (23), including VIM, SNAI1, ECDH and others in human non-small cell cancers. The explanations for reduced survival in patients with EMT signature positive cancers may be related to enhanced motility and chemotherapy resistance characteristic of the mesenchymal state.…”

Active PLK1-driven metastasis is amplified by TGF-β signaling that forms a positive feedback loop in non-small cell lung cancer

“…To understand the expressions of PLK1 during NSCLC metastasis, we leveraged a published transcriptome of several NSCLC cells treated with TGF-β to induce the EMT (GSE 114761) [27] (Fig. 1d).…”

Analysis of genomic and transcriptomic variations as prognostic signature for lung adenocarcinoma

“…DEPTOR was also identified as one of the 77 clinically relevant predictive biomarker at TGFβ-EMT signature generated by microarray analysis of TGFβ-1 treated non-small cell lung cancer cells. TGFβ-EMT gene signature could predicted overall survival and metastasis-free survival in lung adenocarcinoma [26]. MASP-2 (Mannan-binding lectin-associated serine protease 2) is a plasma protein involved in lectin pathway of complement system which promotes cell differentiation, proliferation, migration and reduced apoptosis.…”