journal contribution
posted on 2023-03-30, 23:45 authored by Sebastian Marwitz, Sofia Depner, Dmytro Dvornikov, Ruth Merkle, Magdalena Szczygieł, Karin Müller-Decker, Philippe Lucarelli, Marvin Wäsch, Heimo Mairbäurl, Klaus F. Rabe, Christian Kugler, Ekkehard Vollmer, Martin Reck, Swetlana Scheufele, Maren Kröger, Ole Ammerpohl, Reiner Siebert, Torsten Goldmann, Ursula Klingmüller Activity of the TGF-beta pathway in tumor-free lung and lung cancer (S1); Validation of the microarray data for individual targets with qRT-PCR assay (S2); Expression of EMT-related proteins in human lung tumor tissues and tumor-free lung (S3); Secretion of TGF-beta and expression of the pathway components in NSCLC cell lines (S4); Activation of TGF-beta pathway members and expression of EMT markers in lung cancer cells with BAMBI reconstitution (S5); Verification of DNA methylation values determined by HumanMethylation450K BeadChip analysis by performing bisulfite pyrosequencing (S6); siRNA-mediated knockdown of BAMBI expression in A549 cell line enhances TGF-beta-induced signaling (S7); siRNA-mediated knockdown of BAMBI expression in the squamous cell carcinoma cell line SK-MES1 enhances TGF-beta-induced signaling (S8); Human alveolar epithelial cells type II (AECII) cells express low amount of SMAD3 (S9); GFP- and BAMBI-GFP-positive A549 cells are present in the mice lungs at the time of sacrifice (S10).
Funding
German Center for Lung Research [Deutsches Zentrum für Lungenforschung (DZL)], the German Ministry of Education and Research (BMBF), and in part by the Klara und Werner Kreitz Stiftung
NIH
Helmholtz International Graduate School for Cancer Research at the German Cancer Research Center (DKFZ)
Airway Research Center North (ARCN)
German Center for Lung Research (DZL)
popgen 2.0 network (P2N)
German Ministry for Education and Research
History
ARTICLE 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.
