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

Edna Gordian,William Douglas Cress,Ben C. Creelan,Teresita Muñoz-Antonia,Erin M. Siegel,Eric B. Haura,Nicholas Gimbrone,Eric A. Welsh,David Shibata,Steven A. Eschrich

doi:10.18632/oncotarget.26574

Edna Gordian, William Douglas Cress + Show 8 more

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https://doi.org/10.18632/oncotarget.26574

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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.

Highlights

Early-stage non-small cell lung carcinoma (NSCLC) recurrences are attributable to metastatic disease undetected at the time of resection [1]
We demonstrate that the TGFβEMT signature, in both the microarray and NanoString format, can predict overall survival (OS), and metastasis-free survival (MFS) in patients with Non-Small Cell Lung Carcinoma (NSCLC)
NSCLC cell lines can undergo Transforming Growth Factor β (TGFβ)-induced epithelialto-mesenchymal transition (EMT), implicating EMT in the development of metastasis from the lung [24, 25]; different NSCLC cell lines vary in their responses to TGFβ and in their capacity to undergo TGFβ-induced EMT [26] in vitro

Summary

Introduction

Early-stage non-small cell lung carcinoma (NSCLC) recurrences are attributable to metastatic disease undetected at the time of resection [1]. TGFβ inhibits cell proliferation and induces apoptosis, thereby acting as a tumor suppressor; TGFβ acts as a tumor promoter, as it plays a role at many levels of carcinogenesis. These include epithelial/mesenchymal differentiation via SMADs and PI3K-AKT, angiogenesis via activating vascular endothelial growth factor and metalloproteases [9], and evasion of immune suppression by inhibiting the growth of many hematopoietic cell lines and by impairing T-cell activation [10, 11]

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