Abstract 3395: TGFβ response signature in non-small cell lung carcinoma

Abstract

Abstract Background: Transforming growth factor beta (TGFβ) is a cytokine involved in numerous cellular processes that include proliferation, migration and apoptosis. TGFβ is intriguing in that it plays a dual role in cancer; in some cases it functions as a tumor suppressor while in others it acts as a tumor promoter. Genetic alterations in the TGFβ signaling pathway have been reported in many cancers including breast, colon, gastric, lung, head and neck and pancreatic cancers. Correlations between a TGFβ induced gene expression and clinical outcomes have been described in breast and liver cancers, but not in non-small cell lung cancer (NSCLC). Because TGFβ has been shown to induce an epithelial-to-mesenchymal transition (EMT) in NSCLC that may lead to increased potential to invade and disseminate, we hypothesized that a TGFβ-induced gene expression signature might correlate with this transition and might predict prognosis in NSCLC patients. We therefore decided to attempt to identify gene expression changes induced by TGFβ that correlated with induced proliferation, migration, and EMT. We further investigated whether these TGFβ induced genes might be useful in the classification of NSCLC tumors. Methods: Ten different NSCLC cell lines were assessed for the ability of TGFβ-1 to induce migration, proliferation, and EMT. Cell lines were treated with TGFβ-1 for various time periods and the RNA collected for microarray analysis. Results: In nine out of the ten cell lines the TGFβ pathway was activated after treatment with TGFβ-1, but these lines differ in their TGFβ proliferation, migration and EMT responses. The H1944, H358, and A549 cell lines respond by shifting from an epithelial to a mesenchymal phenotype. Using the before and after treatment samples of these cell lines we looked for genes correlated with this transition. Initially, 632 probesets (534 genes) were identified that changed similarly in these 3 cell lines. Many of these changes seen after 120 hours of treatment were also seen at 48 hours but to a lesser degree. After Principal Component Analysis of the 534 genes in tumor sample a core set of 70 genes were retained and used to analyze lung cancer tumor samples. Using two independently derived sets of lung tumors the EMT signature could be used to identify 3 classes of tumors: tumors with high EMT gene expression, tumors with low EMT expression, and a distinct group of tumors that do not coordinately express the EMT genes identified in this study. Conclusion: Analysis of the differential responses of NSCLC cell lines to TGFβ-1 allows us to group NSCLC cell lines into at least three groups based on their response to TGFβ treatment. Using an EMT signature developed from the cell lines it appears that tumor samples can also be classified into three or more distinct groups that may differ in their in vivo responses to TGFβ-1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3395. doi:1538-7445.AM2012-3395