Voena, ClaudiaVaresio, Lydia M.Zhang, LiyeMenotti, MatteoPoggio, TeresaPanizza, ElenaWang, QiMinero, Valerio G.Fagoonee, SharmilaCompagno, MaraAltruda, FiorellaMonti, StefanoChiarle, Roberto2016-11-182016Voena, C., L. M. Varesio, L. Zhang, M. Menotti, T. Poggio, E. Panizza, Q. Wang, et al. 2016. “Oncogenic ALK regulates EMT in non-small cell lung carcinoma through repression of the epithelial splicing regulatory protein 1.” Oncotarget 7 (22): 33316-33330. doi:10.18632/oncotarget.8955. http://dx.doi.org/10.18632/oncotarget.8955.1949-2553http://nrs.harvard.edu/urn-3:HUL.InstRepos:29408245A subset of Non-Small Cell Lung Carcinoma (NSCLC) carries chromosomal rearrangements involving the Anaplastic Lymphoma Kinase (ALK) gene. ALK-rearranged NSCLC are typically adenocarcinoma characterized by a solid signet-ring cell pattern that is frequently associated with a metastatic phenotype. Recent reports linked the presence of ALK rearrangement to an epithelial-mesenchymal transition (EMT) phenotype in NSCLC, but the extent and the mechanisms of an ALK-mediated EMT in ALK-rearranged NSCLC are largely unknown. We found that the ALK-rearranged H2228 and DFCI032, but not the H3122, cell lines displayed a mesenchymal phenotype. In these cell lines, oncogenic ALK activity dictated an EMT phenotype by directly suppressing E-cadherin and up-regulating vimentin expression, as well as expression of other genes involved in EMT. We found that the epithelial splicing regulatory protein 1 (ESRP1), a key regulator of the splicing switch during EMT, was repressed by EML4-ALK activity. The treatment of NSCLC cells with ALK tyrosine kinase inhibitors (TKIs) led to up-regulation of ESRP1 and E-cadherin, thus reverting the phenotype from mesenchymal to epithelial (MET). Consistently, ESRP1 knock-down impaired E-cadherin up-regulation upon ALK inhibition, whereas enforced expression of ESRP1 was sufficient to increase E-cadherin expression. These findings demonstrate an ALK oncogenic activity in the regulation of an EMT phenotype in a subset of NSCLC with potential implications for the biology of ALK-rearranged NSCLC in terms of metastatic propensity and resistance to therapy.en-USlung cancerALKEMTESRP1/2Journal Article2016-11-1810.18632/oncotarget.8955