Abstract 3418: TWIST1 a new determinant of epithelial to mesenchymal transition in EGFR mutated lung adenocarcinoma

Abstract

Abstract Metastasis, a recognized multistep biological process, is the main cause of mortality in cancer patients. Although EGFR mutated lung cancers are of better prognosis, a group of patients develop metastasis and died of disease. We previously showed that EGFR mutations were associated with a copy number variation at a locus encompassing the TWIST1 gene on chromosome 7. TWIST1 is a highly conserved developmental gene involved in embryogenesis that turned out to be frequently reactived in cancers promoting both malignant conversion and cancer progression. The aim of this study was to investigate the role of TWIST1 on progression in EGFR mutated lung cancer. Using 6 human lung cell lines with or without EGFR mutations or TWIST1 reactivation, we demonstrated that epithelial-mesenchymal transition (EMT) and the associated mobility were dependent upon TWIST1 expression in cells with EGFR mutation. Indeed, EGF treatment only induced EMT and mobility in cells with TWIST reactivation. EGF treatment induced a translocation of TWIST1 to the nucleus, up-regulated mesenchymal markers and down-regulated epithelial markers at mRNA and protein levels. Moreover, inhibition of either the oncogenic EGF pathway stimulation or TWIST1 expression by small RNA technology reversed the phenomenon suggesting that both EGF pathway activation and TWIST1 reactivation are necessary for EMT in lung cancer with EGFR mutation. In a second step, we analyzed surgical lung cancer specimens from non-smokers with and without EGFR mutations and looked for TWIST1 and epithelial or mesenchymal markers expression. Hierarchical clustering combining TWIST1, epithelial (CDH1, JUP) and mesenchymal (VIM, CDH2) gene mRNA expression in tumors perfectly individualizes the EGFR mutated group as the group with TWIST1 reactivation. Immunohistochemical analysis of lung cancer samples revealed that TWIST1 protein expression was associated with EGFR mutation and low CDH1 expression supporting our in vitro observations. Collectively, our observations support that TWIST1 collaborates with EGF/EGFR mutated signaling pathway in promoting EMT in lung cancers and thereby drives the metastatic dissemination in this group of patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3418. doi:10.1158/1538-7445.AM2011-3418