TWIST1 a New Determinant of Epithelial to Mesenchymal Transition in <em>EGFR</em> Mutated Lung Adenocarcinoma

<div><p>Metastasis is a multistep process and the main cause of mortality in lung cancer patients. We previously showed that <em>EGFR</em> mutations were associated with a copy number gain at a locus encompassing the <em>TWIST1</em> gene on chromosome 7. <em>TWIST1</em> is a highly conserved developmental gene involved in embryogenesis that may be reactivated in cancers promoting both malignant conversion and cancer progression through an epithelial to mesenchymal transition (EMT). The aim of this study was to investigate the possible implication of TWIST1 reactivation on the acquisition of a mesenchymal phenotype in <em>EGFR</em> mutated lung cancer. We studied a series of consecutive lung adenocarcinoma from Caucasian non-smokers for which surgical frozen samples were available (n = 33) and showed that TWIST1 expression was linked to <em>EGFR</em> mutations (P<0.001), to low CDH1 expression (P<0.05) and low disease free survival (P = 0.044). To validate that TWIST1 is a driver of EMT in <em>EGFR</em> mutated lung cancer, we used five human lung cancer cell lines and demonstrated that EMT and the associated cell mobility were dependent upon TWIST1 expression in cells with <em>EGFR</em> mutation. Moreover a decrease of EGFR pathway stimulation through EGF retrieval or an inhibition of TWIST1 expression by small RNA technology reversed the phenomenon. Collectively, our <em>in vivo</em> and <em>in vitro</em> findings support that TWIST1 collaborates with the EGF pathway in promoting EMT in EGFR mutated lung adenocarcinoma and that large series of <em>EGFR</em> mutated lung cancer patients are needed to further define the prognostic role of TWIST1 reactivation in this subgroup.</p>