Oncogenic ALK regulates EMT in non-small cell lung carcinoma through repression of the epithelial splicing regulatory protein 1.
A 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.
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.|Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA, USA.
Claudia
C
Voena
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
Lydia M
LM
Varesio
Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA.
Liye
L
Zhang
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
Matteo
M
Menotti
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
Teresa
T
Poggio
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
Elena
E
Panizza
Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA, USA.
Qi
Q
Wang
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
Valerio G
VG
Minero
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Molecular Biotechnology Center, University of Torino, Torino, Italy.
Sharmila
S
Fagoonee
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.|Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA, USA.
Mara
M
Compagno
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Molecular Biotechnology Center, University of Torino, Torino, Italy.
Fiorella
F
Altruda
Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA.
Stefano
S
Monti
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.|Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA, USA.
Roberto
R
Chiarle
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D015703:Antigens, CD; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; D018797:Cell Cycle Proteins; C539364:ESRP1 protein, human; D008869:Microtubule-Associated Proteins; D047428:Protein Kinase Inhibitors; D016601:RNA-Binding Proteins; D014746:Vimentin; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C415585:EML4 protein, human; D012697:Serine Endopeptidases
ALK; EMT; ESRP1/2; lung cancer