title: Downregulation of the TGFβ Pseudoreceptor BAMBI in Non-Small Cell Lung Cancer Enhances TGFβ Signaling and Invasion.
abstract: Non-small cell lung cancer (NSCLC) is characterized by early metastasis and has the highest mortality rate among all solid tumors, with the majority of patients diagnosed at an advanced stage where curative therapeutic options are lacking. In this study, we identify a targetable mechanism involving TGFβ elevation that orchestrates tumor progression in this disease. Substantial activation of this pathway was detected in human lung cancer tissues with concomitant downregulation of BAMBI, a negative regulator of the TGFβ signaling pathway. Alterations of epithelial-to-mesenchymal transition (EMT) marker expression were observed in lung cancer samples compared with tumor-free tissues. Distinct alterations in the DNA methylation of the gene regions encoding TGFβ pathway components were detected in NSCLC samples compared with tumor-free lung tissues. In particular, epigenetic silencing of BAMBI was identified as a hallmark of NSCLC. Reconstitution of BAMBI expression in NSCLC cells resulted in a marked reduction of TGFβ-induced EMT, migration, and invasion in vitro, along with reduced tumor burden and tumor growth in vivo In conclusion, our results demonstrate how BAMBI downregulation drives the invasiveness of NSCLC, highlighting TGFβ signaling as a candidate therapeutic target in this setting. Cancer Res; 76(13); 3785-801. ©2016 AACR.
authors.affiliation: Pathology of the University Hospital of Lübeck and the Leibniz Research Center Borstel, Borstel, Germany. Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Groβhansdorf, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Marwitz
authors.affiliation: Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany. BIOQUANT, University of Heidelberg, Heidelberg, Germany. Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Sofia
authors.initials: S
authors.lastname: Depner
authors.affiliation: Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany. Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Dvornikov
authors.affiliation: Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany. BIOQUANT, University of Heidelberg, Heidelberg, Germany. Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Merkle
authors.affiliation: Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany. Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Szczygieł
authors.affiliation: Tumor Models, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Müller-Decker
authors.affiliation: Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany. Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lucarelli
authors.affiliation: Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany. Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Marvin
authors.initials: M
authors.lastname: Wäsch
authors.affiliation: Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany. Medical Clinic VII, Sports Medicine, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Heimo
authors.initials: H
authors.lastname: Mairbäurl
authors.affiliation: Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Groβhansdorf, Germany. LungenClinic Groβhansdorf, Groβhansdorf, Germany. Christian Albrechts University Kiel, Kiel, Germany.
authors.forename: Klaus F
authors.initials: KF
authors.lastname: Rabe
authors.affiliation: Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Groβhansdorf, Germany. LungenClinic Groβhansdorf, Groβhansdorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kugler
authors.affiliation: Pathology of the University Hospital of Lübeck and the Leibniz Research Center Borstel, Borstel, Germany. Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Groβhansdorf, Germany.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Vollmer
authors.affiliation: Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Groβhansdorf, Germany. LungenClinic Groβhansdorf, Groβhansdorf, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.affiliation: Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Groβhansdorf, Germany. Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Swetlana
authors.initials: S
authors.lastname: Scheufele
authors.affiliation: Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Groβhansdorf, Germany. Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Kröger
authors.affiliation: Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Groβhansdorf, Germany. Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Ole
authors.initials: O
authors.lastname: Ammerpohl
authors.affiliation: Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Groβhansdorf, Germany. Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Pathology of the University Hospital of Lübeck and the Leibniz Research Center Borstel, Borstel, Germany. Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Groβhansdorf, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Goldmann
authors.affiliation: Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany. BIOQUANT, University of Heidelberg, Heidelberg, Germany. Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany. u.klingmueller@dkfz-heidelberg.de.
authors.forename: Ursula
authors.initials: U
authors.lastname: Klingmüller
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000368:Aged; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002465:Cell Movement; D049109:Cell Proliferation; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C485671:BAMBI protein, human; D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta